Substituted piperidine compounds

ABSTRACT

3,4-Disubstituted-4-aryl-piperidine compounds are disclosed. Pharmaceutical compositions containing the 3,4-disubstituted-4-aryl-piperidine compounds and methods of their pharmaceutical uses are also disclosed. The compounds disclosed are useful, inter alia, as antagonists of opioid receptors.

FIELD OF THE INVENTION

The present invention relates to compounds that affect the opioidreceptor system and, more particularly, to3,4-disubstituted-4-aryl-piperidine compounds and pharmaceuticalcompositions containing such compounds that are, inter alia, antagonistsof opioid receptors.

BACKGROUND OF THE INVENTION

It is well known that opioid drugs target three types of endogenousopioid receptors (i.e., μ, δ, and κ receptors) in biological systems.Many opiates, such as morphine, are μ opioid agonists that are oftenused as analgesics for the treatment of severe pain due to theiractivation of μ opioid receptors in the brain and central nervous system(CNS). Opioid receptors are, however, not limited to the CNS, and may befound in other tissues throughout the body, i.e., peripheral to the CNS.A number of side effects of opioid drugs may be caused by activation ofthese peripheral receptors. For example, administration of μ opioidagonists often results in intestinal dysfunction due to the large numberof receptors in the wall of the gut (Wittert, G., Hope, P. and Pyle, D.,Biochemical and Biophysical Research Communications 1996, 218, 877-881;Bagnol, D., Mansour, A., Akil, A. and Watson, S. J., Neuroscience 1997,81, 579-591). Specifically, opioids are generally known to cause nauseaand vomiting, as well as inhibition of normal propulsivegastrointestinal function in animals and man (Reisine, T., andPasternak, G., Goodman & Gilman's The Pharmacological Basis ofTherapeutics, Ninth Edition 1996, 521-555), resulting in side effectssuch as, for example, constipation.

Recent evidence has indicated that naturally-occurring endogenous opioidcompounds may also affect propulsive activity in the gastrointestinal(GI) tract. Met-enkephalin, which activates μ and δ receptors in boththe brain and gut, is one of several neuropeptides found in the GI tract(Koch, T. R., Carney, J. A., Go, V. L., and Szurszewski, J. H.,Digestive Diseases and Sciences 1991, 36, 712-728). Additionally,receptor knockout techniques have shown that mice lacking μ opioidreceptors may have faster GI transit times than wild-type mice,suggesting that endogenous opioid peptides may tonically inhibit GItransit in normal mice (Schuller, A. G. P., King, M., Sherwood, A. C.,Pintar, J. E., and Pasternak, G. W., Society of Neuroscience Abstracts1998, 24, 524). Studies have shown that opioid peptides and receptorslocated throughout the GI tract may be involved in normal regulation ofintestinal motility and mucosal transport of fluids in both animals andman (Reisine, T., and Pasternak, G., Goodman & Gilman's ThePharmacological Basis of Therapeutics, Ninth Edition 1996, 521-555).Other studies show that the sympathetic nervous system may be associatedwith endogenous opioids and control of intestinal motility (Bagnol, D.,Herbrecht, F., Jule, Y., Jarry, T., and Cupo, A., Regul. Pept. 1993, 47,259-273). The presence of endogenous opioid compounds associated withthe GI tract suggests that an abnormal physiological level of thesecompounds may lead to bowel dysfunction.

It is a common problem for patients having undergone surgicalprocedures, especially surgery of the abdomen, to suffer from aparticular bowel dysfunction called post-surgical (or post-operative)ileus. “Ileus,” as used herein, refers to the obstruction of the bowelor gut, especially the colon. See, e.g., Dorland's Illustrated MedicalDictionary, 27th ed., p. 816, (W.B. Saunders Company, Philadelphia, Pa.,1988). Ileus should be distinguished from constipation, which refers toinfrequency of or difficulty in feces evacuation. See, e.g., Dorland'sIllustrated Medical Dictionary, 27th ed., p. 375, (W.B. SaundersCompany, Philadelphia 1988). Ileus may be, diagnosed by the disruptionof normal coordinated movements of the gut, resulting in failure ofintestinal contents propulsion. See, e.g., Resnick, J. Am. J. ofGastroenterology 1997, 92, 751 and Resnick, J. Am. J. ofGastroenterology, 1997, 92, 934. In some instances, particularlyfollowing surgery, including surgery of the abdomen, the boweldysfunction may become quite severe, lasting for more than a week andaffecting more than one portion of the GI tract. This condition is oftenreferred to as post-surgical (or post-operative) paralytic ileus andmost frequently occurs after laparotomy (see Livingston, E. H. andPassaro, Jr., E. D., Digestive Diseases and Sciences 1990, 35, 121).Similarly, post-partum ileus is a common problem for women in the periodfollowing childbirth, and is thought to be caused by similarfluctuations in natural opioid levels as a result of birthing stress.

Gastrointestinal dysmotility associated with post-surgical ileus isgenerally most severe in the colon and typically lasts for 3 to 5 days.The administration of opioid analgesics to a patient after surgery mayoften contribute to bowel dysfunction, thereby delaying recovery ofnormal bowel function. Since virtually all patients receive opioidanalgesics, such as morphine or other narcotics, for pain relief aftersurgery, particularly major surgery, current post-surgical paintreatment may actually slow recovery of normal bowel function, resultingin a delay in hospital discharge and increasing the cost of medicalcare.

Post-surgical and post-partum ileus may also occur in the absence ofexogenous opioid agonists. It would be of benefit to inhibit the naturalactivity of endogenous opioids during and/or after periods of biologicalstress, such as surgery and childbirth, so that ileus and related formsof bowel dysfunction can be prevented and/or treated. Currently,therapies for ileus include functional stimulation of the intestinaltract, stool softeners, laxatives, lubricants, intravenous hydration,and nasogastric decompression. These prior art methods suffer fromdrawbacks, for example, as lacking specificity for post-surgical orpost-partum ileus. And these prior art methods offer no means forprevention. If ileus could be prevented, hospital stays, recovery times,and medical costs would be significantly decreased, in addition to thebenefit of minimizing patient discomfort. Thus, drugs that selectivelyact on opioid receptors in the gut would be ideal candidates forpreventing and/or treating post-surgical and post-partum ileus. Ofthose, drugs that do not interfere with the effects of opioid analgesicsin the CNS would be of special benefit in that they may be administeredsimultaneously for pain management with limited side effects.

Peripheral opioid antagonists that do not cross the blood-brain barrierinto the CNS are known in the literature and have been tested inrelation to their activity on the GI tract. In U.S. Pat. Nos. 5,250,542,5,434,171, 5,159,081, and 5,270,328, peripherally selectivepiperidine-N-alkylcarboxylate opioid antagonists are described as beinguseful in the treatment of idiopathic constipation, irritable bowelsyndrome and opioid-induced constipation. Also, U.S. Pat. No. 4,176,186describes quaternary derivatives of noroxymorphone (i.e.,methylnaltrexone) that are said to prevent or relieve the intestinalimmobility side-effect of narcotic analgesics without reducing analgesiceffectiveness. U.S. Pat. No. 5,972,954 describes the use ofmethylnaltrexone, enteric coated methylnaltrexone, or other quaternaryderivatives of noroxymorphone for preventing and/or treating opioid-and/or nonopioid-induced side effects associated with opioidadministration.

General opioid antagonists, such as naloxone and naltrexone, have alsobeen implicated as being useful in the treatment of GI tractdysmotility. For example, U.S. Pat. No. 4,987,126 and Kreek, M. J.Schaefer, R. A., Hahn, E. F., Fishman, J. Lancet 1983, 1(8319), 261disclose naloxone and other morphinan-based opioid antagonists (i.e.,naloxone, naltrexone) for the treatment of idiopathic gastrointestinaldysmotility. In addition, naloxone has been shown to effectively treatnon-opioid induced bowel obstruction, implying that the drug may actdirectly on the GI tract or in the brain (Schang, J. C., Devroede, G.Am. J. Gastroenerol. 1985, 80(6), 407). Furthermore, it has beenimplicated that naloxone may provide therapy for paralytic ileus (Mack,D. J. Fulton, J. D. Br. J. Surg. 1989, 76(10), 1101). However, it iswell known that activity of naloxone and related drugs is not limited toperipheral systems and may interfere with the analgesic effects ofopioid narcotics.

Inasmuch as post-surgical and post-partum ileus, for example, are commonillnesses that add to the cost of health care and as yet have nospecific treatments, there is a need for a specific and effectiveremedy. The majority of currently known opioid antagonist therapies isnot peripherally selective and has the potential for undesirable sideeffects resulting from penetration into the CNS. Given the estimated 21million inpatient surgeries and 26 million outpatient surgeries eachyear, and an estimate of 4.7 million patients experiencing post-surgicalileus, methods involving opioid antagonists that are not only specificfor peripheral systems, but specific for the gut, are desirable fortreating post-surgical and post-partum ileus.

There is still an unfulfilled need for compounds that may be used inmethods to antagonize opioid receptors, particularly where undesirablesymptoms or conditions are side effects of administering exogenousopioids. The present invention is directed to these, as well as otherimportant ends.

SUMMARY OF THE INVENTION

Accordingly, the present invention is directed, in part, to novelpharmaceutically active compounds of formula I:

wherein:

-   -   R¹ is —C(═O)OR⁵, —C(═O)NR⁶R⁷, —NR⁶R⁷, or —CH₂OR⁵;    -   R² and R³ are each independently alkyl or alkenyl;    -   R⁴ is:        -   H,        -   cycloalkyl,        -   heterocycloalkyl, or        -   C₁₋₁₀ alkyl which is substituted with at least one:            -   substituted aryl, wherein at least one of said aryl                substituents is other than OH, nitro, amino, halo, CN,                CH₂CN, CONH₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, or C₁₋₅ alkanoyl                (which latter three groups are optionally substituted by                one or more halo atoms),            -   aryloxyaryl,            -   -aryl-N(H)R^(b),            -   -aryl-N(R^(b))R^(b),            -   heteroarylaryl,            -   alkoxyaryl, wherein the carbon chain of said alkoxy is                interrupted by a nitrogen atom,            -   substituted alkoxyaryl, provided that when one or more                substituents are present on the alkoxy group, at least                one of said substituents is other than halo,            -   substituted cycloalkyl,            -   RS(═O)_(p) substituted heteroaryl,            -   RS(═O)_(p) substituted heterocycloalkyl,            -   RS(═O)_(p) substituted aryl,            -   heterocycloalkylheteroaryl,            -   heteroarylheteroaryl,            -   bicycloalkyl,            -   bicycloalkenyl,            -   carboxy,            -   —CO₂R^(a),            -   —C(═O)N(R^(6a))—R^(6b)—CO₂H,            -   —C(═O)N(R^(6a))—R^(6b)—CO₂R,            -   —C(═O)N(R^(6a))—R^(6b)—C(═O)NR^(7a)R^(7b),            -   —N(R^(7c))C(═O)R^(7d),            -   —N(R^(7c))S(═O)₂R^(7d),            -   aralkoxyaryl,            -   substituted arylheteroaryl, or            -   substituted alkoxyheteroaryl, provided that when one or                more substituents are present on the alkoxy group, at                least one of said substituents is other than halo;    -   p is 0, 1, or 2;        -   R is alkyl, aralkyl, or aryl;        -   R^(a) is H, alkyl, alkenyl, cycloalkyl, aryl, or heteroaryl,            provided that R^(a) is not C₁₋₆ alkyl;    -   each R^(b) is independently alkyl, cycloalkyl, aralkyl, or aryl,    -   R^(6a) is H, alkyl, aralkyl, cycloalkyl, alkenyl, aryl,        heteroaralkyl, or heteroaryl;    -   R^(6b) is lower alkylene, or lower aralkylene or, together with        the nitrogen atom to which they are attached, R^(6a) and R^(6b)        form a 4- to 7-membered heterocycloalkyl ring;    -   R^(7a) and R^(7b) are each independently H, alkyl, cycloalkyl,        heterocycloalkyl, heteroaryl, aralkyl, or aryl, or together with        the nitrogen atom to which they are attached, R^(7a) and R^(7b)        form a 4- to 7-membered heterocycloalkyl ring, provided that at        least one of R^(7a) and R^(7b) is other than H;    -   R^(7c) and R^(7d) are each independently H, alkyl, cycloalkyl,        heterocycloalkyl, heteroaryl, aralkyl, or aryl;    -   R⁵ is H or alkyl; and    -   each is R⁶ and R⁷ independently H, alkyl, or —C(═O)R, or        together with the nitrogen atom to which they are attached, R⁶        and R⁷ form a 4- to 7-membered heterocycloalkyl ring, provided        that no more than one of R⁶ and R⁷ is —C(═O)R, and provided that        when R¹ is NR⁶R⁷, R⁴ can also be aralkyl;

or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,solvate, acid salt hydrate, N-oxide or isomorphic crystalline formthereof, provided that R² and R³ are not in the cis stereoisomerconformation when both R² and R³ are methyl.

In another embodiment, the invention is directed to pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and aneffective amount of a compound of formula I.

In yet another embodiment, the invention is directed to methods forbinding opioid receptors, preferably μ or κ opioid receptors, in apatient in need thereof.

In other embodiments, the invention is directed to methods for bindingopioid receptors, where the 3,4-disubstituted-4-aryl-piperidine compoundexhibits activity toward the opioid receptors (selected from μ, κ, orcombinations thereof).

In some preferred embodiments, the invention is directed to methodswhere the patient is in need of prevention or treatment of a condition,disease or undesirable side effect caused by an endogenous or exogenousopioid.

In a particularly preferred embodiment, the invention is directed tomethods for preventing or treating gastrointestinal dysfunction.

In yet another preferred embodiment, the invention is directed tomethods of preventing or treating pain, comprising the step of:

administering to a patient in need thereof, a composition, comprising aneffective amount of an opioid; and an effective amount of a compound offormula I.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

As employed above and throughout the disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings.

As used herein, “alkyl” refers to an optionally substituted, saturatedstraight, branched, or cyclic hydrocarbon having from about 1 to about20 carbon atoms (and all combinations and subcombinations of ranges andspecific numbers of carbon atoms therein), with from about 1 to about 8carbon atoms, herein referred to as “lower alkyl”, being preferred.Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, cyclopentyl, isopentyl,neopentyl, n-hexyl, isohexyl, cyclohexyl, cyclooctyl, adamantyl,3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.

As used herein, “alkylene” refers to a bivalent alkyl radical having thegeneral formula —(CH₂)_(n)—, where n is 1 to 10. Non-limiting examplesinclude methylene, trimethylene, pentamethylene, and hexamethylene.Alkylene groups can be optionally substituted. The term “lower alkylene”herein refers to those alkylene groups having from about 1 to about 6carbon atoms.

As used herein, “aralkylene” refers to a bivalent alkyl radical havingthe general formula —(CH₂)_(n)—, wherein any one of the hydrogens on thealkylene radical is replaced by an aryl group, and where n is 1 to 10.Aralkylene groups can be optionally substituted. Non-limiting examplesinclude phenylmethylene, 2-phenyltrimethylene,3-(p-anisyl)-pentamethylene, and2-(m-trifluromethylphenyl)-hexamethylene. Aralkylene groups can besubstituted or unsubstituted. The term “lower aralkylene” herein refersto those aralkylene groups having from about 1 to about 6 carbon atomsin the alkylene portion of the aralkylene group.

As used herein, “alkenyl” refers to an alkyl group having one or moredouble bonds, wherein alkyl is as previously defined. Alkenyl groups canbe optionally substituted.

As used herein, “aryl” refers to an optionally substituted, mono-, di-,tri-, or other multicyclic aromatic ring system having from about 5 toabout 50 carbon atoms (and all combinations and subcombinations ofranges and specific numbers of carbon atoms therein), with from about 6to about 10 carbons being preferred. Non-limiting examples include, forexample, phenyl, naphthyl, anthracenyl, and phenanthrenyl.

As used herein, “aralkyl” refers to alkyl radicals bearing an arylsubstituent and have from about 6 to about 50 carbon atoms (and allcombinations and subcombinations of ranges and specific numbers ofcarbon atoms therein), with from about 6 to about 10 carbon atoms beingpreferred. Aralkyl groups can be optionally substituted. Non-limitingexamples include, for example, benzyl, diphenylmethyl, triphenylmethyl,phenylethyl, and diphenylethyl.

As used herein, “heteroaryl” refers to an optionally substituted, mono-,di-, tri-, or other multicyclic aromatic ring system that includes atleast one, and preferably from 1 to about 4 sulfur, oxygen, or nitrogenheteroatom ring members. Heteroaryl groups can have, for example, fromabout 3 to about 50 carbon atoms (and all combinations andsubcombinations of ranges and specific numbers of carbon atoms therein),with from about 4 to about 10 carbons being preferred. Non-limitingexamples of heteroaryl groups include, for example, pyrryl, furyl,pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl,imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl,thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl,carbazolyl, benzimidazolyl, and isoxazolyl.

As used herein, “cycloalkyl” refers to an optionally substituted, alkylgroup having one or more rings in their structures having from about 3to about 20 carbon atoms (and all combinations and subcombinations ofranges and specific numbers of carbon atoms therein), with from about 3to about 10 carbon atoms being preferred. Multi-ring structures may bebridged or fused ring structures. groups include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, andadamantyl.

As used herein, “alkylcycloalkyl” refers to an optionally substitutedring system comprising a cycloalkyl group having one or more alkylsubstituents. Exemplary alkylcycloalkyl groups include2-methylcyclohexyl, 3,3-dimethylcyclopentyl,trans-2,3-dimethylcyclooctyl, and 4-methyldecahydronaphthalenyl.

As used herein, “heteroaralkyl” refers to an optionally substituted,heteroaryl substituted alkyl radicals having from about 2 to about 50carbon atoms (and all combinations and subcombinations of ranges andspecific numbers of carbon atoms therein), with from about 6 to about 25carbon atoms being preferred. Non-limiting examples include2-(1H-pyrrol-3-yl)ethyl, 3-pyridylmethyl, 5-(2H-tetrazolyl)methyl, and3-(pyrimidin-2-yl)-2-methylcyclopentanyl.

As used herein, “heterocycloalkyl” refers to an optionally substituted,mono-, di-, tri-, or other multicyclic aliphatic ring system thatincludes at least one, and preferably from 1 to about 4 sulfur, oxygen,or nitrogen heteroatom ring members. Heterocycloalkyl groups can havefrom about 3 to about 20 carbon atoms (and all combinations andsubcombinations of ranges and specific numbers of carbon atoms therein),with from about 4 to about 10 carbons being preferred. Theheterocycloalkyl group may be unsaturated, and may also be fused toaromatic rings. Examples of heterocycloalkyl groups include, forexample, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, piperazinyl, morpholinyl, piperadinyl,decahydroquinolyl, octahydrochromenyl, octahydro-cyclopenta[c]pyranyl,1,2,3,4,-tetrahydroquinolyl, 3-(1,2,3,4,-tetrahydro-7-hydroxyquinolyl),3-(1,2,3,4,-tetrahydro-7-hydroxy-N-methylquinolyl),3-(1,2,3,4,-tetrahydro-7-hydroxy-N-acetylquinolyl),octahydro-[2]pyrindinyl, decahydro-cycloocta[c]furanyl, andimidazolidinyl.

As used herein, the term “spiroalkyl” refers to an optionallysubstituted, alkylene diradical, both ends of which are bonded to thesame carbon atom of the parent group to form a spirocyclic group. Thespiroalkyl group, taken together with its parent group, as hereindefined, has 3 to 20 ring atoms. Preferably, it has 3 to 10 ring atoms.Non-limiting examples of a spiroalkyl group taken together with itsparent group include 1-(1-methyl-cyclopropyl)-propan-2-one,2-(1-phenoxy-cyclopropyl)-ethylamine, and 1-methyl-spiro [4.7]dodecane.

As used herein, the term “alkoxy” refers to an optionally substitutedalkyl-O— group wherein alkyl is as previously defined. Exemplary alkoxygroups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, andheptoxy.

As used herein, the term “aryloxy” refers to an optionally substitutedaryl-O— group wherein aryl is as previously defined. Exemplary aryloxygroups include phenoxy and naphthoxy.

As used herein, the term “aralkoxy” refers to an optionally substitutedaralkyl-O— group wherein aralkyl is as previously defined. Exemplaryaralkoxy groups include benzyloxy, 1-phenylethoxy, 2-phenylethoxy, and3-naphthylheptoxy.

As used herein, the term “aryloxyaryl” refers to an aryl group with anaryloxy substituent wherein aryloxy and aryl are as previously defined.Aryloxyaryl groups can be optionally substituted. Exemplary aryloxyarylgroups include phenoxyphenyl, and naphthoxyphenyl.

As used herein, the term “heteroarylaryl” refers to an aryl group with aheteroaryl substituent wherein heteroaryl and aryl are as previouslydefined. Heteroarylaryl groups can be optionally substituted. Exemplaryheteroarylaryl groups include 3-pyridylphenyl, 2-quinolylnaphthalenyl,and 2-pyrrolylphenyl.

As used herein, the term “alkoxyaryl” refers to an aryl group bearing analkoxy substituent wherein alkoxy and aryl are as previously defined.Alkoxyaryl groups can be optionally substituted. Exemplary alkoxyarylgroups include para-anisyl, meta-t-butoxyphenyl, andmethylendioxyphenyl.

As used herein, the term “carbon chain of said alkoxy interrupted by anitrogen atom” refers to a carbon chain of an alkoxy group, wherein anitrogen atom has been inserted between two adjacent carbon atoms of thecarbon chain and wherein alkoxy is as previously defined. Both thealkoxy group and the nitrogen atom can be optionally substituted.Exemplary groups include —OCH₂CH₂N(CH₃)CH₂CH₃ and —OCH₂CH₂NHCH₃.

As used herein, the term “heterocycloalkylheteroaryl” refers to anheteroaryl group with a heterocycloalkyl substituent whereinheterocycloalkyl and heteroaryl are as previously defined.Heterocycloalkylheteroaryl groups can be optionally substituted.Exemplary heterocycloalkylheteroaryl groups include3-[N-morpholinyl]pyridine and 3-[2-piperidinyl]pyridine.

As used herein, the term “heteroarylheteroaryl” refers to an heteroarylgroup with an heteroaryl substituent wherein heteroaryl is as previouslydefined. Heteroarylherteroaryl groups can be optionally substituted.Exemplary heteroarylheteroaryl groups include 4-[3-pyridyl]pyridine and2-[2-quinolyl]quinuclidine.

As used herein, the term “aralkoxyaryl” refers to an aryl group with anaralkoxy substituent wherein aralkoxy and aryl are as previouslydefined. Aralkoxyaryl groups can be optionally substituted. Exemplaryaralkoxyaryl groups include benzyloxyphenyl and meta-toluenyloxyphenyl.

As used herein, the term “arylheteroaryl” refers to an heteroaryl groupwith an aryl substituent wherein aryl and heteroaryl are as previouslydefined. Arylheteroaryl groups can be optionally substituted. Exemplaryarylheteroaryl groups include 3-phenylpyridyl and2-naphthalenylquinolinyl.

As used herein, the term “alkoxyheteroaryl” refers to an heteroarylgroup with an alkoxy substituent wherein alkoxy and heteroaryl are aspreviously defined. Alkoxyheteroaryl groups can be optionallysubstituted. Exemplary alkoxyheteroaryl groups include 2-methoxypyridineand 6-n-propoxyquinoline.

As used herein, “bicycloalkyl” refers to an optionally substituted,alkyl group having two bridged rings in its structure and having fromabout 7 to about 20 carbon atoms (and all combinations andsubcombinations of ranges and specific numbers of carbon atoms therein),with from about 7 to about 15 carbon atoms being preferred. Exemplarybicycloalkyl-ring structures include, but are not limited to, norboinyl,bomyl, [2.2.2]-bicyclooctyl, cis-pinanyl, trans-pinanyl, camphanyl,iso-bomyl, and fenchyl.

As used herein, “bicycloalkenyl” refers to an optionally substituted,alkenyl group having two bridged rings in its structure and having fromabout 7 to about 20 carbon atoms (and all combinations andsubcombinations of ranges and specific numbers of carbon atoms therein),with from about 7 to about 15 carbon atoms being preferred. Exemplarybicycloalkenyl-ring structures include, but are not limited to,bicyclo[2.2.1]hept-5-en-2-yl, bornenyl, [2.2.2]-bicyclooct-5-en-2-yl,alpha-pinenyl, beta-pinenyl, camphenyl, and fenchyl.

As used herein, “carboxy” refers to a —C(═O)OH group.

As used herein, “alkanoyl” refers to a —C(═O)-alkyl group, wherein alkylis as previously defined. Exemplary alkanoyl groups include acetyl(ethanoyl), n-propanoyl, n-butanoyl, 2-methylpropanoyl, n-pentanoyl,2-methylbutanoyl, 3-methylbutanoyl, 2,2-dimethylpropanoyl, heptanoyl,and decanoyl.

Typically, substituted chemical moieties include one or moresubstituents that replace hydrogen. Exemplary substituents include, forexample, halo (e.g. F, Cl, Br, I), alkyl, cycloalkyl, alkylcycloalkyl,alkenyl, alkynyl, aralkyl, aryl, heteroaryl, heteroaralkyl, spiroalkyl,heterocycloalkyl, hydroxyl (—OH), nitro (—NO₂), cyano (—CN), amino(—NH₂), —N-substituted amino (—NHR″), -N,N-disubstituted amino(—N(R″)R″), carboxyl (—COOH), —C(═O)R″, —OR″, —C(═O)OR″, —NHC(═O)R″,aminocarbonyl (—C(═O)NH₂), —N-substituted aminocarbonyl (—C(═O)NHR″),-N,N-disubstituted aminocarbonyl (—C(═O)N(R″)R″), thiol, thiolato (SR″),sulfonic acid (SO₃H), phosphonic acid (PO₃H), S(═O)₂R″, S(═O)₂NH₂,S(═O)₂ NHR″, S(═O)₂NR″R″, NHS(═O)₂R″, NR″S(═O)₂R″, CF₃, CF₂CF₃,NHC(═O)NHR″, NHC(═O)NR″R″, NR″C(═O)NHR″, NR″C(═O)NR″R″, NR″C(═O)R″ andthe like. In relation to the aforementioned substituents, each moiety R″can be, independently, any of H, alkyl, cycloalkyl, alkenyl, aryl,aralkyl, heteroaryl, or heterocycloalkyl, for example.

“Side effect” refers to a consequence other than the one(s) for which anagent or measure is used, as the adverse effects produced by a drug,especially on a tissue or organ system other then the one sought to bebenefited by its administration. In the case, for example, of opioids,the term “side effect” may refer to such conditions as, for example,constipation, nausea and/or vomiting.

“Effective amount” refers to an amount of a compound as described hereinthat may be therapeutically effective to inhibit, prevent or treat thesymptoms of particular disease, disorder or side effect. Such diseases,disorders and side effects include, but are not limited to, thosepathological conditions associated with the administration of opioids(for example, in connection with the treatment and/or prevention ofpain), wherein the treatment or prevention comprises, for example,inhibiting the activity thereof by contacting cells, tissues orreceptors with compounds of the present invention. Thus, for example,the term “effective amount”, when used in connection with opioids, forexample, for the treatment of pain, refers to the treatment and/orprevention of the painful condition. The term “effective amount”, whenused in connection with opioid antagonist compounds, refers to thetreatment and/or prevention of side effects typically associated withopioids including, for example, such side effects as constipation,nausea and/or vomiting, as well as other side effects, discussed infurther detail below.

“Pharmaceutically acceptable” refers to those compounds, materials,compositions, and/or dosage forms which are, within the scope of soundmedical judgment, suitable for contact with the tissues of human beingsand animals without excessive toxicity, irritation, allergic response,or other problem complications commensurate with a reasonablebenefit/risk ratio.

“In combination with”, “combination therapy” and “combination products”refer, in certain embodiments, to the concurrent administration to apatient of opioids and the compounds of formula (I). When administeredin combination, each component may be administered at the same time orsequentially in any order at different points in time. Thus, eachcomponent may be administered separately but sufficiently closely intime so as to provide the desired therapeutic effect.

“Dosage unit” refers to physically discrete units suited as unitarydosages for the particular individual to be treated. Each unit maycontain a predetermined quantity of active compound(s) calculated toproduce the desired therapeutic effect(s) in association with therequired pharmaceutical carrier. The specification for the dosage unitforms of the invention may be dictated by (a) the unique characteristicsof the active compound(s) and the particular therapeutic effect(s) to beachieved, and (b) the limitations inherent in the art of compoundingsuch active compound(s).

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like. These physiologically acceptable salts are prepared bymethods known in the art, e.g., by dissolving the free amine bases withan excess of the acid in aqueous alcohol, or neutralizing a freecarboxylic. acid with an alkali metal base such as a hydroxide, or withan amine.

Compounds described herein throughout, can be used or prepared inalternate forms. For example, many amino-containing compounds can beused or prepared as an acid addition salt. Often such salts improveisolation and handling properties of the compound. For example,depending on the reagents, reaction conditions and the like, compoundsas described herein can be used or prepared, for example, as theirhydrochloride or tosylate salts. Isomorphic crystalline forms, allchiral and racemic forms, N-oxide, hydrates, solvates, and acid salthydrates, are also contemplated to be within the scope of the presentinvention.

Certain acidic or basic compounds of the present invention may exist aszwitterions. All forms of the compounds, including free acid, free baseand zwitterions, are contemplated to be within the scope of the presentinvention. It is well known in the art that compounds containing bothamino and carboxyl groups often exist in equilibrium with theirzwitterionic forms. Thus, any of the compounds described hereinthroughout that contain, for example, both amino and carboxyl groups,also include reference to their corresponding zwitterions.

“Patient” refers to animals, including mammals, preferably humans.

“Prodrug” refers to compounds specifically designed to maximize theamount of active species that reaches the desired site of reaction whichare of themselves typically inactive or minimally active for theactivity desired, but through biotransformation are converted intobiologically active metabolites.

“Stereoisomers” refers to compounds that have identical chemicalconstitution, but differ as regards the arrangement of the atoms orgroups in space.

“N-oxide” refers to compounds wherein the basic nitrogen atom of eithera heteroaromatic ring or tertiary amine is oxidized to give a quaternarynitrogen bearing a positive formal charge and an attached oxygen atombearing a negative formal charge.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

The piperidines of the invention as illustrated in formula I can occuras the trans and cis stereochemical isomers at the 3- and 4-positions ofthe piperidine ring. The term “trans” as used herein refers to the R²substituent being on the opposite side of the R³ substituent, whereas inthe “cis” isomer, the R² substituent and the R³ substituent are on thesame side of the ring. The present invention contemplates the individualstereoisomers, as well as racemic mixtures. In the most preferredcompounds of the present invention, the R² substituent and the R³substituent are in the “trans” orientation on the piperidine.

In addition to the “cis” and trans” orientation of the R² substituentand the R³ substituent, the absolute stereochemistry of the carbon atomsbearing the R² substituent and the R³ substituent is also defined asusing the commonly employed “R” and “S” definitions (Orchin et al., TheVocabulary of Organic Chemistry, John Wiley and Sons, Inc., page 126,which is incorporated herein by reference). The preferred compounds ofthe present invention are those of formula I in which the configurationof both the R² substituent and the R³ substituent on the piperidine ringis “R”.

Furthermore, asymmetric carbon atoms may be introduced into the moleculedepending on the structure of R⁴. As such, these classes of compoundscan exist as the individual “R” or “S” stereoisomers at these chiralcenters, or the racemic mixture of the isomers, and all are contemplatedas within the scope of the present invention. Preferably, asubstantially pure stereoisomer of the compounds of this invention isused, i.e., an isomer in which the configuration at the chiral center is“R” or “S”, i.e., those compounds in which the configuration at thethree chiral centers I preferably 3R, 4R, S or 3R, 4R, R.

In certain preferred embodiments, the compounds, pharmaceuticalcompositions and methods of the present invention may involve aperipheral opioid antagonist compound. The term “peripheral” designatesthat the compound acts primarily on physiological systems and componentsexternal to the central nervous system. In preferred form, theperipheral opioid antagonist compounds employed in the methods of thepresent invention exhibit high levels of activity with respect toperipheral tissue, such as, gastrointestinal tissue, while exhibitingreduced, and preferably substantially no, CNS activity. The phrase“substantially no CNS activity,” as used herein, means that less thanabout 20% of the pharmacological activity of the compounds employed inthe present methods is exhibited in the CNS, preferably less than about15%, more preferably less than about 10%, even more preferably less thanabout 5% and most preferably 0% of the pharmacological activity of thecompounds employed in the present methods is exhibited in the CNS.

Furthermore, it is preferred in certain embodiments of the inventionwhere the compound is administered to antagonize the peripheral sideeffects of an opioid that the compound does not substantially cross theblood-brain barrier and thereby decrease the beneficial activity of theopioid. The phrase “does not substantially cross,” as used herein, meansthat less than about 20% by weight of the compound employed in thepresent methods crosses the blood-brain barrier, preferably less thanabout 15% by weight, more preferably less than about 10% by weight, evenmore preferably less than about 5% by weight and most preferably 0% byweight of the compound crosses the blood-brain barrier. Selectedcompounds can be evaluated for CNS penetration by determining plasma andbrain levels following i.v. administration.

Accordingly, in one embodiment, the present invention provides novelpharmaceutically active compounds of formula I:

wherein:

-   -   R¹ is —C(═O)OR⁵, —C(═O)NR⁶R⁷, —NR⁶R⁷ or —CH₂OR⁵;    -   R² and R³ are each independently alkyl or alkenyl;    -   R⁴ is        -   H,        -   cycloalkyl,        -   heterocycloalkyl, or        -   C₁₋₁₀ alkyl which is substituted with at least one:            -   substituted aryl, wherein at least one of said aryl                substituents is other than OH, nitro, amino, halo, CN,                CH₂CN, CONH₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, or C₁₋₅ alkanoyl                (which latter three groups are optionally substituted by                one or more halo atoms),            -   aryloxyaryl,            -   -aryl-N(H)R^(b),            -   -aryl-N(R^(b))R^(b),            -   heteroarylaryl,            -   alkoxyaryl, wherein the carbon chain of said alkoxy is                interrupted by a nitrogen atom,            -   substituted alkoxyaryl, provided that when one or more                substituents are present on the alkoxy group, at least                one of said substituents is other than halo,            -   substituted cycloalkyl,            -   RS(═O)_(p) substituted heteroaryl,            -   RS(═O)_(p) substituted heterocycloalkyl,            -   RS(═O)_(p) substituted aryl,            -   heterocycloalkylheteroaryl,            -   heteroarylheteroaryl,            -   bicycloalkyl,            -   bicycloalkenyl,            -   carboxy,            -   —CO₂R^(a),            -   —C(═O)N(R^(6a))—R^(6b)—CO₂H,            -   —C(═O)N(R^(6a))—R^(6b)—CO₂R,            -   —C(═O)N(R^(6a))—R^(6b)—C(═O)NR^(7a)R^(7b),            -   —N(R^(7c))C(═O)R^(7d),            -   —N(R^(7c))S(═O)₂R^(7d),            -   aralkoxyaryl,            -   substituted arylheteroaryl, or            -   substituted alkoxyheteroaryl, provided that when one or                more substituents are present on the alkoxy group, at                least one of said substituents is other than halo;    -   p is 0, 1, or 2;    -   R is alkyl, aralkyl, or aryl;    -   R^(a) is H, alkyl, alkenyl, cycloalkyl, aryl, or heteroaryl,        provided that R^(a) is not C₁₋₆ alkyl;    -   each R^(b) is independently alkyl, cycloalkyl, aralkyl, or aryl,    -   R^(6a) is H, alkyl, aralkyl, cycloalkyl, alkenyl, aryl,        heteroaralkyl, or heteroaryl;    -   R^(6b) is lower alkylene, or lower aralkylene or, together with        the nitrogen atom to which they are attached, R^(6a) and R^(6b)        form a 4- to 7-membered heterocycloalkyl ring;    -   R^(7a) and R^(7b) are each independently H, alkyl, cycloalkyl,        heterocycloalkyl, heteroaryl, aralkyl, or aryl or, together with        the nitrogen atom to which they are attached, R^(7a) and R^(7b)        form a 4- to 7-membered heterocycloalkyl ring, provided that at        least one of R^(7a) and R^(7b) is other than H;    -   R^(7c) and R^(7d) are each independently H, alkyl, cycloalkyl,        heterocycloalkyl, heteroaryl, aralkyl, or aryl;    -   R⁵ is H or alkyl; and    -   each R⁶ and R⁷ is independently H, alkyl, or —C(═O)R, or        together with the nitrogen atom to which they are attached, R⁶        and R⁷ form a 4- to 7-membered heterocycloalkyl ring, provided        that no more than one of R⁶ and R⁷ is —C(═O)R, and provided that        when R¹ is NR⁶R⁷, R⁴ can also be aralkyl;

or a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate,solvate, acid salt hydrate, N-oxide or isomorphic crystalline formthereof, provided that R² and R³ are not in the cis stereoisomerconformation when both R² and R³ are methyl.

In certain preferred embodiments, R¹ is —C(═O)OR⁵, —C(═O)NR⁶R⁷, or—NR⁶R⁷.

Also in the above compounds of formula I, R² and R³ are eachindependently alkyl or alkenyl. Preferably, R² and R³ are eachindependently alkyl. Even more preferably, R² and R³ are methyl.

Also in the above compounds of formula I, preferably, R⁴ is:

-   -   H,    -   cycloalkyl,    -   heterocycloalkyl, or    -   C₁₋₁₀ alkyl which is substituted with at least one:        -   substituted aryl, wherein said aryl substituent is other            than OH, nitro, amino, halo, CN, CH₂CN, CONH₂, C₁₋₄ alkyl,            C₁₋₄ alkoxy, or C₁₋₅ alkanoyl (which latter three groups are            optionally substituted by one or more halo atoms),        -   aryloxyaryl,        -   -aryl-N(H)R^(b),        -   -aryl-N(R^(b))R^(b),        -   heteroarylaryl,        -   alkoxyaryl, wherein the carbon chain of said alkoxy is            interrupted by a nitrogen atom,        -   substituted alkoxyaryl, provided that when one or more            substituents are present on the alkoxy group, at least one            of said substituents is other than halo,        -   substituted cycloalkyl,        -   RS(═O)_(p) substituted heteroaryl,        -   RS(═O)_(p) substituted heterocycloalkyl,        -   RS(═O)_(p) substituted aryl,        -   heterocycloalkylheteroaryl,        -   heteroarylheteroaryl,        -   bicycloalkyl,        -   bicycloalkenyl,        -   carboxy,        -   —CO₂R^(a),        -   —C(═O)N(R^(6a))—R^(6b)—CO₂H,        -   —C(═O)N(R^(6a))—R^(6b)—CO₂R,        -   —C(═O)N(R^(6a))—R^(6b)—C(═O)NR^(7a)R^(7b),        -   —N(R^(7c))C(═O)R^(7d),        -   —N(R^(7c))S(═O)₂R^(7d),        -   aralkoxyaryl,        -   substituted arylheteroaryl, or        -   substituted alkoxyheteroaryl, provided that when one or more            substituents are present on the alkoxy group, at least one            of said substituents is other than halo.

Even more preferably, R⁴ is:

-   -   H,    -   cycloalkyl,    -   heterocycloalkyl, or    -   C₁₋₁₀ alkyl which is substituted with at least one:        -   aryloxyaryl,        -   -aryl-N(H)R^(b),        -   -aryl-N(R^(b))R^(b),        -   heteroarylaryl,        -   alkoxyaryl, wherein the carbon chain of said alkoxy is            interrupted by a nitrogen atom,        -   substituted cycloalkyl,        -   RS(═O)_(p) substituted heteroaryl,        -   RS(═O)_(p) substituted heterocycloalkyl,        -   RS(═O)_(p) substituted aryl,        -   heterocycloalkylheteroaryl,        -   heteroarylheteroaryl,        -   bicycloalkyl,        -   bicycloalkenyl,        -   carboxy,        -   —CO₂R^(a),        -   —C(═O)N(R^(6a))—R^(6b)—CO₂H,        -   —C(═O)N(R^(6a))—R^(6b)—CO₂R,        -   —C(═O)N(R^(6a))—R^(6b)—C(═O)NR^(7a)R^(7b),        -   —N(R^(7c))C(═O)R^(7d),        -   aralkoxyaryl, or        -   substituted arylheteroaryl.            Most preferably, R⁴ is —(CH₂)_(n)—CH(R⁸)—C(═O)OR⁹,            —(CH₂)_(n)—CH(R⁸)—C(═O)NR¹⁰NR¹¹, or            —(CH₂)_(n)—CH(R⁸)—(CH₂)_(m)—NR¹⁹R²⁰.

In certain preferred embodiments of the compounds of formula I, R⁴ is

wherein:

-   -   R⁸ is alkyl, aralkyl, cycloalkyl, alkylcycloalkyl, aryl,        heteroaryl, or heteroaralkyl;    -   R⁹ is H, alkyl, alkenyl, cycloalkyl, aryl, or heteroaryl; and    -   n is an integer from 1 to 3;    -   provided that R⁹ is not C₁₋₆ alkyl.

In certain other preferred embodiments of the compounds of formula I, R⁴is

In yet other preferred embodiments of the compounds of formula I, R⁴ is

wherein:

-   -   R⁸ is alkyl, aralkyl, cycloalkyl, alkylcycloalkyl, aryl,        heteroaryl, or heteroaralkyl;    -   R¹⁰ is —R^(6b)—CO₂H, —R^(6b)—CO₂R^(10a), or        —R^(6b)—C(═O)NR^(10b)R^(10c);    -   R¹¹ is H, alkyl, alkenyl, cycloalkyl, aryl, aralkyl,        heteroaralkyl or heteroaryl, or together with the nitrogen atom        to which they are attached, R^(6b) and R¹¹ form a 4- to        7-membered heterocycloalkyl ring, or;    -   R^(10a) is alkyl or aralkyl;    -   R^(10b) and R^(10c) are each independently H or alkyl, or        together with the nitrogen atom to which they are attached,        R^(10b) and R^(10c) form a 4- to 7-membered heterocycloalkyl        ring, provided that at least one of R^(10b) and R^(10c) is other        than H; and    -   n is an integer from 1 to 3.

In other preferred embodiments of the compounds of formula I, R⁴ is

wherein:

-   -   R¹² is H, lower alkyl, or aralkyl;    -   R¹³ is H, alkyl, cycloalkyl, or aryl, or together with the        nitrogen and carbon atoms to which they are respectively        attached, R¹² and R¹³ form a 4- to 7-membered heterocycloalkyl        ring;    -   each R¹⁴ independently is H, alkyl, cycloalkyl or aryl;    -   R¹⁵ is —OR¹⁶ or —NR¹⁷R¹⁸;    -   R¹⁶, R¹⁷, and R¹⁸ are each, independently H, or alkyl or,        together with the nitrogen atom to which they are attached, R¹⁷        and R¹⁸ form a 4- to 7-membered heterocycloalkyl ring; and    -   m is an integer from 0 to 3;    -   provided that at least one of R¹⁷ and R¹⁸ is other than H.

In still other preferred embodiments of the compounds of formula I, R⁴is

wherein:

-   -   R⁸ is alkyl, aralkyl, cycloalkyl, alkylcycloalkyl, or aryl;    -   R¹⁹ is H, alkyl, cycloalkyl, or aryl;    -   R²⁰ is —C(═O)R²¹, or —S(═O)₂R²¹,    -   R²¹ is alkyl, cycloalkyl, heterocycloalkyl, aralkyl, aryl, or        heteroaryl;    -   m is an integer from 0 to 3; and    -   n is an integer from 1 to 3.

In other preferred embodiments of the compounds of formula I, R⁴ is

wherein:

-   -   R¹⁹ is H or alkyl.

In the above compounds of formula I, R⁵ is H or alkyl.

Also in the above compounds of formula I, R⁶ and R⁷ are eachindependently H, alkyl, or —C(═O)R, or together with the nitrogen atomto which they are attached, R⁶ and R⁷ form a 4- to 7-memberedheterocycloalkyl ring, provided that no more than one of R⁶ and R⁷ is—C(═O)R, and provided that when R¹ is —NR⁶R⁷, R⁴ can also be aralkyl.

In yet other preferred embodiments of the compounds of formula I, R¹ is—C(═O)OR⁵, —C(═O)NR⁶R⁷; or —NR⁶R⁷, and R⁴ is C₁₋₁₀ alkyl, which issubstituted with —N(R^(7c))C(═O)R^(7d), —C(═O)N(R^(6a))—R^(6b)—CO₂H, or—C(═O)N(R^(6a))—R^(6b)—CO₂R. More preferably, R⁴, R⁵, and R⁶ are H.

The above compounds of formula I also include but are not limited toother forms, such as their stereoisomers, prodrugs, pharmaceuticallyacceptable salt, hydrate, solvate, acid salt hydrate, N-oxide orisomorphic crystalline form thereof, provided that R² and R³ are not inthe cis stereoisomer conformation when both R² and R³ are methyl.

In a more preferred embodiment of the present invention, there areprovided compounds of the formula I which have the following formula Ia:

More preferably, the compounds of formula Ia have the following formulaIIa:

wherein:

-   -   R⁸ is alkyl, aralkyl, cycloalkyl, alkylcycloalkyl, aryl,        heteroaryl, or heteroaralkyl;    -   R⁹ is H, alkyl, alkenyl, cycloalkyl, aryl, or heteroaryl; and    -   n is an integer from 1 to 3;        provided that R⁹ is not C₁₋₆ alkyl.

In the above compounds of formula IIa, R⁸ is alkyl, aralkyl, cycloalkyl,alkylcycloalkyl, aryl, heteroaryl, or heteroaralkyl. Preferably, R⁸ isaralkyl, and R⁹ is H or alkyl, provided that R⁹ is not C₁₋₆ alkyl. Morepreferably, the compounds of the formula IIa have the following formulaIIIa:

In another more preferred embodiment of the present invention, there areprovided compounds of the formula Ia which have the following formulaIVa:

wherein:

-   -   R⁸ is alkyl, aralkyl, cycloalkyl, alkylcycloalkyl, aryl,        heteroaryl, or heteroaralkyl;    -   R¹⁰ is —R^(6b)—CO₂H, —R^(6b)—CO₂R^(10a), or        —R^(6b)—C(═O)NR^(10b)R^(10c);    -   R¹¹ is H, alkyl, alkenyl, cycloalkyl, aryl, aralkyl,        heteroaralkyl or heteroaryl, or together with the nitrogen atom        to which they are attached, R^(6b) and R¹¹ form a 4- to        7-membered heterocycloalkyl ring;    -   R^(10a) is alkyl or aralkyl;    -   R^(10b) and R^(10c) are each independently H or alkyl, or        together with the nitrogen atom to which they are attached,        R^(10b) and R^(10c) form a 4- to 7-membered heterocycloalkyl        ring, provided that at least one of R^(10b) and R^(10c) is other        than H; and    -   n is an integer from 1 to 3.

In the above compounds of formula IVa, preferably R⁸ is aralkyl. Morepreferably, R⁸ is benzyl, and n is 1. More preferably, the compounds offormula IVa have the following formula Va:

wherein:

-   -   R¹² is H, lower alkyl, or aralkyl;    -   R¹³ is H, alkyl, cycloalkyl, or aryl, or together with the        nitrogen and carbon atoms to which they are respectively        attached, R¹² and R¹³ form a 4- to 7-membered heterocycloalkyl        ring;    -   each R¹⁴ independently is H, alkyl, cycloalkyl or aryl;    -   R¹⁵ is —OR¹⁶ or —NR¹⁷R¹⁸;    -   R¹⁶, R¹⁷, and R¹⁸ are each, independently H, or alkyl or,        together with the nitrogen atom to which they are attached, R¹⁷        and R¹⁸ form a 4- to 7-membered heterocycloalkyl ring; and    -   m is an integer from 0 to 3;        provided that at least one of R¹⁷ and R¹⁸ is other than H.

In another more preferred embodiment of the present invention, there areprovided compounds of the formula Ia which have the following formulaVIa:

wherein:

-   -   R⁸ is alkyl, aralkyl, cycloalkyl, alkylcycloalkyl, or aryl;    -   R¹⁹ is H, alkyl, cycloalkyl, or aryl;    -   R²⁰ is —C(O)R²¹, or —S(═O)₂R²¹;    -   R²¹ is alkyl, cycloalkyl, heterocycloalkyl, aralkyl, aryl, or        heteroaryl;    -   m is an integer from 0 to 3; and        n is an integer from 1 to 3.

In the above compounds of formula VIa, preferably R⁸ is alkyl. Morepreferably R⁸ is isopropyl and R¹⁹ is H or alkyl. Even more preferably,n is 1. Most preferably, the compounds of formula VIa have the followingformula VIIa:

wherein:

-   -   R¹⁹ is H or alkyl.

In certain preferred embodiments of the compound of formula I,

-   -   R¹ is —C(O)OR⁵, —C(O)NR⁶R⁷ or —NR⁶R⁷; and    -   R⁴ is C₁₋₁₀ alkyl, which is substituted with        —N(R^(7c))C(═O)R^(7d), —C(═O)N(R^(6a))—R^(6b)—CO₂H, or        —C(═O)N(R^(6a))—R^(6b)—CO₂R. More preferably, R⁴ is C₁₋₁₀ alkyl,        which is substituted with —N(R^(7c))C(═O)R^(7d). Even more        preferably, when R⁴ is C₁₋₁₀ alkyl, which is substituted with        —N(R^(7c))C(═O)R^(7d), R⁵, R⁶, and R⁷ are H.

In other more preferred embodiments of the compound of formula I,

-   -   R¹ is —C(O)OR5, —C(O)NR⁶R⁷ or —NR⁶R⁷; and    -   R⁴ is C₁₋₁₀ alkyl, which is substituted with        —C(═O)N(R^(6a))—R^(6b)—CO₂H. Even more preferably, when R⁴ is        C₁₋₁₀ alkyl, which is substituted with        —C(═O)N(R^(6a))—R^(6b)—CO₂H, R⁵, R⁶, and R⁷ are H.

In still other more preferred embodiments of the compound of formula I,

-   -   R¹ is —C(O)OR5, —C(═O)NR⁶R⁷ or —NR⁶R⁷; and    -   R⁴ is C₁₋₁₀ alkyl, which is substituted with        —C(═O)N(R^(6a))—R^(6b)—CO₂R. Even more preferably, when R⁴ is        C₁₋₁₀ alkyl, which is substituted with        —C(═O)N(R^(6a))—R^(6b)—CO₂R, R⁵, R⁶, and R⁷ are H.

In certain preferred embodiments of the compound of formula Ia,

-   -   R¹ is —C(═O)OR5, —C(═O)NR⁶R⁷ or —NR⁶R⁷; and    -   R² and R³ are methyl, and    -   R⁴ is C₁₋₁₀ alkyl, which is substituted with        —N(R^(7c))C(═O)R^(7d), —C(═O)N(R^(6a))—R^(6b)—CO₂H, or        —C(═O)N(R^(6a))—R^(6b)—CO₂R. More preferably, R⁴ is C₁₋₁₀ alkyl,        which is substituted with —N(R^(7c))C(═O)R^(7d). Even more        preferably, when R⁴ is C₁₋₁₀ alkyl, which is substituted with        —N(R^(7c))C(═O)R^(7d), R⁵, R⁶, and R⁷ are H.

In other preferred embodiments of the compound of formula Ia,

-   -   R¹ is —C(═O)OR5, —C(═O)NR⁶R⁷ or —NR⁶R⁷; and    -   R² and R³ are methyl; and    -   R⁴ is C₁₋₁₀ alkyl, which is substituted with        —C(═O)N(R^(6a))—R^(6b)—CO₂H. Even more preferably, when R⁴ is        C₁₋₁₀ alkyl, which is substituted with        —C(═O)N(R^(6a))—R^(6b)—CO₂H, R⁵, R⁶, and R⁷ are H.

In still other preferred embodiments of the compound of formula Ia,

-   -   R¹ is —C(═O)OR5, —C(═O)NR⁶R⁷ or —NR⁶R⁷; and    -   R² and R³ are methyl; and    -   R⁴ is C₁₋₁₀ alkyl, which is substituted with        —C(═O)N(R^(6a))—R^(6b)—CO₂R. Even more preferably, when R⁴ is        C₁₋₁₀ alkyl, which is substituted with        —C(═O)N(R^(6a))—R^(6b)—CO₂R, R⁵, R⁶, and R⁷ are H.

The compounds employed in the methods of the present invention may existin prodrug form. As used herein, “prodrug” is intended to include anycovalently bonded carriers which release the active parent drug, forexample, as according to formula I or other formulas or compoundsemployed in the methods of the present invention in vivo when suchprodrug is administered to a mammalian subject. Since prodrugs are knownto enhance numerous desirable qualities of pharmaceuticals (e.g.,solubility, bioavailability, manufacturing, etc.) the compounds employedin the present methods may, if desired, be delivered in prodrug form.Thus, the present invention contemplates methods of delivering prodrugs.Prodrugs of the compounds employed in the present invention, for exampleformula I, may be prepared by modifying functional groups present in thecompound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent compound.

Accordingly, prodrugs include, for example, compounds described hereinin which a hydroxy, amino, or carboxy group is bonded to any group that,when the prodrug is administered to a mammalian subject, cleaves to forma free hydroxyl, free amino, or carboxylic acid, respectively. Examplesinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups; and alkyl,carbocyclic, aryl, and alkylaryl esters such as methyl, ethyl, propyl,iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl,benzyl, and phenethyl esters, and the like.

The compounds employed in the methods of the present invention may beprepared in a number of ways well known to those skilled in the art. Thecompounds can be synthesized, for example, by the methods describedbelow, or variations thereon as appreciated by the skilled artisan. Allprocesses disclosed in association with the present invention arecontemplated to be practiced on any scale, including milligram, gram,multigram, kilogram, multikilogram or commercial industrial scale.

As discussed in detail above, compounds employed in the present methodsmay contain one or more asymmetrically substituted carbon atoms, and maybe isolated in optically active or racemic forms. Thus, all chiral,diastereomeric, racemic forms and all geometric isomeric forms of astructure are intended, unless the specific stereochemistry or isomericform is specifically indicated. It is well known in the art how toprepare and isolate such optically active forms. For example, mixturesof stereoisomers may be separated by standard techniques including, butnot limited to, resolution of racemic forms, normal, reverse-phase, andchiral chromatography, preferential salt formation, recrystallization,and the like, or by chiral synthesis either from chiral startingmaterials or by deliberate synthesis of target chiral centers.

As will be readily understood, functional groups present may containprotecting groups during the course of synthesis. Protecting groups areknown per se as chemical functional groups that can be selectivelyappended to and removed from functionalities, such as hydroxyl groupsand carboxyl groups. These groups are present in a chemical compound torender such functionality inert to chemical reaction conditions to whichthe compound is exposed. Any of a variety of protecting groups may beemployed with the present invention. Preferred protecting groups includethe benzyloxycarbonyl group and the tert-butyloxycarbonyl group. Otherpreferred protecting groups that may be employed in accordance with thepresent invention may be described in Greene, T. W. and Wuts, P. G. M.,Protective Groups in Organic Synthesis 2d. Ed., Wiley & Sons, 1991.

The 3,4-disubstituted-4-aryl piperidine compounds according to thepresent invention may be synthesized employing methods taught, forexample, in U.S. Pat. Nos. 5,250,542, 5,434,171, 5,159,081, and5,270,328, the disclosures of which are hereby incorporated herein byreference in their entireties. The optically active(+)-4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidine was employed asstarting material in the synthesis of the present compounds may beprepared by the general procedure taught in J. Org. Chem., 1991, 56,1660-1663, U.S. Pat. No. 4,115,400 and U.S. Pat. No. 4,891,379, thedisclosures of which are hereby incorporated herein by reference intheir entireties.

While not intending to be bound by any theory or theories of operation,it is contemplated that opioid side effects, such as constipation,vomiting and nausea, may result from undesirable interaction of theopioid with peripheral opioid receptors, such as peripheral Z receptors.Administration of the compounds of formula I according to one aspect ofthe present invention may block interaction of the opioid compounds withthe peripheral receptors, thereby preventing and/or inhibiting the sideeffects, while preferably not interfering with the therapeutic effect ofthe opioid in the CNS.

In accordance with certain embodiments of the present invention, thereare provided methods which comprise administering to a patient, interalia, an opioid compound. A wide variety of opioids are available whichmay be suitable for use in the present methods and compositions.Generally speaking, it is only necessary that the opioid provide thedesired effect (for example, pain alleviation), and be capable of beingincorporated into the present combination products and methods(discussed in detail below). In preferred embodiments, the presentmethods and compositions may involve an opioid which is selected fromalfentanil, buprenorphine, butorphanol, codeine, dezocine,dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol,meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone,oxymorphone, pentazocine, propiram, propoxyphene, sufentanil and/ortramadol. More preferably, the opioid is selected from morphine,codeine, oxycodone, hydrocodone, dihydrocodeine, propoxyphene, fentanyland/or tramadol.

The opioid component of the present compositions may further include oneor more other active ingredients that may be conventionally employed inanalgesic and/or cough-cold-antitussive combination products. Suchconventional ingredients include, for example, aspirin, acetaminophen,phenylpropanolamine, phenylephrine, chlorpheniramine, caffeine, and/orguaifenesin. Typical or conventional ingredients that may be included inthe opioid component are described, for example, in the Physicians' DeskReference, 1999, the disclosure of which is hereby incorporated hereinby reference, in its entirety.

In addition, the opioid component may further include one or morecompounds that may be designed to enhance the analgesic potency of theopioid and/or to reduce analgesic tolerance development. Such compoundsinclude, for example, dextromethorphan or other NMDA antagonists (Mao,M. J. et al., Pain 1996, 67, 361), L-364,718 and other CCK antagonists(Dourish, C. T. et al., Eur J Pharmacol 1988, 147, 469), NOS inhibitors(Bhargava, H. N. et al., Neuropeptides 1996, 30, 219), PKC inhibitors(Bilsky, E. J. et al., J. Pharmacol Exp Ther 1996, 277, 484), anddynorphin antagonists or antisera (Nichols, M. L. et al., Pain 1997, 69,317). The disclosures of each of the foregoing documents are herebyincorporated herein by reference, in their entireties.

Other opioids, optional conventional opioid components, and optionalcompounds for enhancing the analgesic potency of the opioid and/or forreducing analgesic tolerance development, that may be employed in themethods and compositions of the present invention, in addition to thoseexemplified above, would be readily apparent to one of ordinary skill inthe art, once armed with the teachings of the present disclosure.

Another embodiment of the invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and aneffective amount of a compound of formula I.

Yet another embodiment of the invention provides a method for treatingor preventing opioid-bowel dysfunction comprising the step ofadministering to a patient in need of such treatment a compositioncomprising an opioid and an effective amount of a compound of formula I.

Still another embodiment of the invention provides a method for treatingor preventing ileus comprising the step of administering to a patient inneed of such treatment, an effective amount of a compound of formula I.

Another embodiment of the invention provides a method for treating orpreventing a side effect associated with an opioid comprising the stepof administering to a patient, an effective amount of a compound offormula I.

Although the compounds of the present invention may be administered asthe pure chemicals, it is preferable to present the active ingredient asa pharmaceutical composition. The invention thus further provides apharmaceutical composition comprising one or more of the compounds offormula I, together with one or more pharmaceutically acceptablecarriers therefore and, optionally, other therapeutic and/orprophylactic ingredients. The carrier(s) must be acceptable in the senseof being compatible with the other ingredients of the composition andnot deleterious to the recipient thereof.

The compounds of the invention may be administered in an effectiveamount by any of the conventional techniques well-established in themedical field. The compounds employed in the methods of the presentinvention including, for example, opioid and the compounds of formula I,may be administered by any means that results in the contact of theactive agents with the agents' site or site(s) of action in the body ofa patient. The compounds may be administered by any conventional meansavailable for use in conjunction with pharmaceuticals, either asindividual therapeutic agents or in a combination of therapeutic agents.For example, they may be administered as the sole active agents in apharmaceutical composition, or they can be used in combination withother therapeutically active ingredients.

The compounds are preferably combined with a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice as described, for example, in Remington'sPharmaceutical Sciences (Mack Pub. Co., Easton, Pa., 1980), thedisclosures of which are hereby incorporated herein by reference, intheir entirety.

Compounds of the present invention can be administered to a mammalianhost in a variety of forms adapted to the chosen route ofadministration, e.g., orally or parenterally. Parenteral administrationin this respect includes administration by the following routes:intravenous, intramuscular, subcutaneous, intraocular, intrasynovial,transepithelial including transdermal, ophthalmic, sublingual andbuccal; topically including ophthalmic, dermal, ocular, rectal and nasalinhalation via insufflation, aerosol and rectal systemic.

The active compound may be orally administered, for example, with aninert diluent or with an assimilable edible carrier, or it may beenclosed in hard or soft shell gelatin capsules, or it may be compressedinto tablets, or it may be incorporated directly with the food of thediet. For oral therapeutic administration, the active compound may beincorporated with excipient and used in the form of ingestible tablets,buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,and the like. The amount of active compound(s) in such therapeuticallyuseful compositions is preferably such that a suitable dosage will beobtained. Preferred compositions or preparations according to thepresent invention may be prepared so that an oral dosage unit formcontains from about 0.1 to about 1000 mg of active compound.

The tablets, troches, pills, capsules and the like may also contain oneor more of the following: a binder, such as gum tragacanth, acacia, cornstarch or gelatin; an excipient, such as dicalcium phosphate; adisintegrating agent, such as corn starch, potato starch, alginic acidand the like; a lubricant, such as magnesium stearate; a sweeteningagent such as sucrose, lactose or saccharin; or a flavoring agent, suchas peppermint, oil of wintergreen or cherry flavoring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with shellac,sugar or both. A syrup or elixir may contain the active compound,sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring, such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form ispreferably pharmaceutically pure and substantially non-toxic in theamounts employed. In addition, the active compound may be incorporatedinto sustained-release preparations and formulations.

The active compound may also be administered parenterally orintraperitoneally. Solutions of the active compounds as free bases orpharmacologically acceptable salts can be prepared in water suitablymixed with a surfactant, such as hydroxypropylcellulose. A dispersioncan also be prepared in glycerol, liquid polyethylene glycols andmixtures thereof and in oils. Under ordinary conditions of storage anduse, these preparations may contain a preservative to prevent the growthof microorganisms.

The pharmaceutical forms suitable for injectable use include, forexample, sterile aqueous solutions or dispersions and sterile powdersfor the extemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form is preferably sterile and fluid toprovide easy syringability. It is preferably stable under the conditionsof manufacture and storage and is preferably preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier may be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycol and the like), suitable mixtures thereof, andvegetable oils. The proper fluidity can be maintained, for example, bythe use of a coating, such as lecithin, by the maintenance of therequired particle size in the case of a dispersion, and by the use ofsurfactants. The prevention of the action of microorganisms may beachieved by various antibacterial and antifungal agents, for example,parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like.In many cases, it will be preferable to include isotonic agents, forexample, sugars or sodium chloride. Prolonged absorption of theinjectable compositions may be achieved by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions may be prepared by incorporating the activecompounds in the required amounts, in the appropriate solvent, withvarious of the other ingredients enumerated above, as required, followedby filtered sterilization. Generally, dispersions may be prepared byincorporating the sterilized active ingredient into a sterile vehiclewhich contains the basic dispersion medium and the required otheringredients from those enumerated above. In the case of sterile powdersfor the preparation of sterile injectable solutions, the preferredmethods of preparation may include vacuum drying and the freeze dryingtechnique that yields a powder of the active ingredient, plus anyadditional desired ingredient from the previously sterile-filteredsolution thereof.

The therapeutic compounds of this invention may be administered to apatient alone or in combination with a pharmaceutically acceptablecarrier. As noted above, the relative proportions of active ingredientand carrier may be determined, for example, by the solubility andchemical nature of the compounds, chosen route of administration andstandard pharmaceutical practice.

The dosage of the compounds of the present invention that will be mostsuitable for prophylaxis or treatment will vary with the form ofadministration, the particular compound chosen and the physiologicalcharacteristics of the particular patient under treatment. Generally,small dosages may be used initially and, if necessary, increased bysmall increments until the desired effect under the circumstances isreached. Generally speaking, oral administration may require higherdosages.

The combination products of this invention, such as pharmaceuticalcompositions comprising opioids in combination with the compounds offormula I, may be in any dosage form, such as those described herein,and can also be administered in various ways, as described herein. In apreferred embodiment, the combination products of the invention areformulated together, in a single dosage form (that is, combined togetherin one capsule, tablet, powder, or liquid, etc.). When the combinationproducts are not formulated together in a single dosage form, the opioidcompounds and the compounds of formula I may be administered at the sametime (that is, together), or in any order. When not administered at thesame time, preferably the administration of an opioid and the compoundsof formula I occurs less than about one hour apart, more preferably lessthan about 30 minutes apart, even more preferably less than about 15minutes apart, and still more preferably less than about 5 minutesapart. Preferably, administration of the combination products of theinvention is oral, although other routes of administration, as describedabove, are contemplated to be within the scope of the present invention.Although it is preferable that the opioids and the compounds of formulaI are both administered in the same fashion (that is, for example, bothorally), if desired, they may each be administered in different fashions(that is, for example, one component of the combination product may beadministered orally, and another component may be administeredintravenously). The dosage of the combination products of the inventionmay vary depending upon various factors such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration, the age, health and weight of the recipient, the natureand extent of the symptoms, the kind of concurrent treatment, thefrequency of treatment, and the effect desired.

Although the proper dosage of the combination products of this inventionwill be readily ascertainable by one skilled in the art, once armed withthe present disclosure, by way of general guidance, where an opioidcompounds is combined with the compounds of formula I, for example,typically a daily dosage may range from about 0.01 to about 100milligrams of the opioid (and all combinations and subcombinations ofranges therein) and about 0.001 to about 100 milligrams of the compoundsof formula I (and all combinations and subcombinations of rangestherein), per kilogram of patient body weight. Preferably, the a dailydosage may be about 0.1 to about 10 milligrams of the opioid and about0.01 to about 10 milligrams of the compounds of formula I per kilogramof patient body weight. Even more preferably, the daily dosage may beabout 1.0 milligrams of the opioid and about 0.1 milligrams of thecompounds of formula I per kilogram of patient body weight. With regardto a typical dosage form of this type of combination product, such as atablet, the opioid compounds (e.g., morphine) generally may be presentin an amount of about 15 to about 200 milligrams, and the compounds offormula I in an amount of about 0.1 to about 4 milligrams.

Particularly when provided as a single dosage form, the potential existsfor a chemical interaction between the combined active ingredients (forexample, an opioid and the compounds of formula I). For this reason, thepreferred dosage forms of the combination products of this invention areformulated such that although the active ingredients are combined in asingle dosage form, the physical contact between the active ingredientsis minimized (that is, reduced).

In order to minimize contact, one embodiment of this invention where theproduct is orally administered provides for a combination productwherein one active ingredient is enteric coated. By enteric coating oneor more of the active ingredients, it is possible not only to minimizethe contact between the combined active ingredients, but also, it ispossible to control the release of one of these components in thegastrointestinal tract such that one of these components is not releasedin the stomach but rather is released in the intestines. Anotherembodiment of this invention where oral administration is desiredprovides for a combination product wherein one of the active ingredientsis coated with a sustained-release material that effects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a low-viscosity grade ofhydroxypropyl methylcellulose (HPMC) or other appropriate materials asknown in the art, in order to further separate the active components.The polymer coating serves to form an additional barrier to interactionwith the other component.

Dosage forms of the combination products of the present inventionwherein one active ingredient is enteric coated can be in the form oftablets such that the enteric coated component and the other activeingredient are blended together and then compressed into a tablet orsuch that the enteric coated component is compressed into one tabletlayer and the other active ingredient is compressed into an additionallayer. Optionally, in order to further separate the two layers, one ormore placebo layers may be present such that the placebo layer isbetween the layers of active ingredients. In addition, dosage forms ofthe present invention can be in the form of capsules wherein one activeingredient is compressed into a tablet or in the form of a plurality ofmicrotablets, particles, granules or non-perils, which are then entericcoated. These enteric coated microtablets, particles, granules ornon-perils are then placed into a capsule or compressed into a capsulealong with a granulation of the other active ingredient.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Pharmaceutical kits useful in, for example, the treatment of pain, whichcomprise a therapeutically effective amount of an opioid along with atherapeutically effective amount of the3,4-disubstituted-4-aryl-piperidine compound of the invention, in one ormore sterile containers, are also within the ambit of the presentinvention. Sterilization of the container may be carried out usingconventional sterilization methodology well known to those skilled inthe art. The sterile containers of materials may comprise separatecontainers, or one or more multi-part containers, as exemplified by theUNIVIAL™ two-part container (available from Abbott Labs, Chicago, Ill.),as desired. The opioid compound and the compounds of formula I may beseparate, or combined into a single dosage form as described above. Suchkits may further include, if desired, one or more of variousconventional pharmaceutical kit components, such as for example, one ormore pharmaceutically acceptable carriers, additional vials for mixingthe components, etc., as will be readily apparent to those skilled inthe art. Instructions, either as inserts or as labels, indicatingquantities of the components to be administered, guidelines foradministration, and/or guidelines for mixing the components, may also beincluded in the kit.

It will be further appreciated that the amount of the compound, or anactive salt or derivative thereof, required for use in treatment willvary not only with the particular salt selected but also with the routeof administration, the nature of the condition being treated and the ageand condition of the patient and will be ultimately at the discretion ofthe attendant physician or clinician.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

The dose may also be provided by controlled release of the compound, bytechniques well known to those in the art.

The compounds of the present invention may be used in methods to bindopioid receptors, including μ and κ opioid receptors. Such binding maybe accomplished by contacting the receptor with an effective amount ofthe compound of the invention. Preferably, the contacting step conductedin an aqueous medium, preferably at physiologically relevant ionicstrength, pH, and the like.

In certain preferred embodiments, the compounds of the present inventionbind μ and κ opioid receptors or combinations thereof. The opioidreceptors may be located in the central nervous system or locatedperipherally to the central nervous system or in both locations.

In certain other preferred embodiments, the compounds of the presentinvention bind κ opioid receptors.

In preferred embodiments of the methods of the invention, the compoundsantagonize the activity of the opioid receptors. In other preferredembodiments, the compounds prevent or treat a condition or diseasecaused by an opioid (either endogenous or exogenous). In certainembodiments of the method, particularly where the opioid are exogenous,the compounds of the invention preferably do not substantially cross theblood-brain barrier.

The compounds of the present invention may be used in methods toantagonize μ, κ or both types of opioid receptors, particularly whereundesirable symptoms or conditions are side effects of administeringexogenous opioids. Furthermore, the compounds of the invention may beused as to treat patients having disease states that are ameliorated bybinding opioid receptors or in any treatment wherein temporarysuppression of the μ, κ or both types of opioid receptor system isdesired.

Such symptoms, conditions or diseases include the complete or partialantagonism of opioid-induced sedation, confusion, respiratorydepression, euphoria, dysphoria, hallucinations, pruritus (itching),increased biliary tone, increased biliary colic, and urinary retention,ileus, emesis, and addiction liability; prevention or treatment ofopioid and cocaine dependence; rapid opioid detoxification; treatment ofalcoholism; treatment of alcoholic coma; detection of opioid use orabuse (pupil test); treatment of eating disorders; treatment of obesity;treatment of post-concussional syndrome; adjunctive therapy in septic,hypovolemic or endotoxin-induced shock; potentiation of opioid analgesia(especially at ultra-low doses); reversal or prevention of opioidtolerance and physical dependence (especially at ultra-low doses);prevention of sudden infant death syndrome; treatment of psychosis(especially wherein the symptoms are associated with schizophrenia,schizophreniform disorder, schizoaffective disorder, unipolar disorder,bipolar disorder, psychotic depression, Alzheimer's disease, Parkinson'sdisease, compulsive disorders, and other psychiatric or neurologicdisorders with psychosis as symptoms); treatment of dyskinesia,treatment of autism; treatment of the endocrine system (includingincreased release of leutinizing hormone, treatment of infertility,increasing number of multiple births in animal husbandry, and male andfemale sexual behavior); treatment of the immune system and cancersassociated with binding of the opioid receptors; treatment ofanxiolysis; treatment of diuresis; treatment and regulation of bloodpressure; treatment of tinnitus or impaired hearing; treatment ofepilepsy; treatment of cachexia; treatment of general cognitivedysfunctions; and treatment of kleptomania.

The compounds of the invention present invention may also be used ascytostatic agents, as antimigraine agents, as immunomodulators, asimmunosuppressives, as antiarthritic agents, as antiallergic agents, asvirucides, to treat diarrhea, antipsychotics, as antischizophrenics, asantidepressants, as uropathic agents, as antitussives, as antiaddictiveagents, as anti-smoking agents, to treat alcoholism, as hypotensiveagents, to treat and/or prevent paralysis resulting from traumaticischemia, general neuroprotection against ischemic trauma, as adjunctsto nerve growth factor treatment of hyperalgesia and nerve grafts, asanti-diuretics, as stimulants, as anti-convulsants, or to treat obesity.Additionally, the present compounds may be used in the treatment ofParkinson” disease as an adjunct to L-dopa for treatment dyskinesiaassociated with the L-dopa treatment.

In certain preferred embodiments, the compounds of the invention may beused in methods for preventing or treating gastrointestinal dysfunction,including, but not limited to, irritable bowel syndrome, opioid-boweldysfunction, colitis, post-operative and opioid-induced emesis (nauseaand vomiting), decreased gastric motility and emptying, inhibition ofsmall and/or large intestinal propulsion, increased amplitude ofnon-propulsive segmental contractions, constriction of sphincter ofOddi, increased anal sphincter tone, impaired reflex relaxation withrectal distention, diminished gastric, biliary, pancreatic or intestinalsecretions, increased absorption of water from bowel contents,gastro-esophageal reflux, gastroparesis, cramping, bloating, abdominalor epigastric pain and discomfort, constipation, and delayed absorptionof orally administered medications or nutritive substances.

In certain preferred embodiments, the compounds of the invention may beused in methods for preventing or treating post-operative oropioid-induced ileus.

In other preferred embodiments, the compounds of the invention may beused in an effective amount in a method in combination with an effectiveamount of an opioid to treat pain.

The compounds of the invention may be administered before, during orafter administering at least one opioid. The methods of the inventionare particularly effective for opioids selected from alfentanil,buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl,hydrocodone, hydromorphone, levorphanol, meperidine (pethidine),methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine,propiram, propoxyphene, sufentanil, tramadol or mixtures thereof.

A series of N-substituted (+)-4(R)-(3-substitutedphenyl)-3(R),4-dimethyl-1-piperidine derivatives (Formula I) wereprepared according to the Schemes 1-9. The derivatives of formula I (R¹is COOR⁵) were prepared according to the Schemes 1-4.

The key intermediate 7 used as starting material for the solid phasesynthesis of compounds of Formula I (R¹ is CONH₂, COOR⁵) was prepared in6 steps from (+)-4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidine (1)(Scheme 1). Condensation of 1 (J. Org. Chem., 1991, 56, 1660-1663) withtert-butyloxycarbonylanhydride afforded the tert-butyloxycarbonyl(Boc)-protected derivative 2 which was converted to the triflate 3 usingN-phenyltrifluoromethane sulfonimide in a halogenated solvent such asdichloromethane and a tertiary amine base such as triethylamine.Palladium catalyzed carbonylation of 3 afforded the methyl ester 4 whichwas converted to the secondary amine 5 by acidic cleavage of the Bocprotecting group. Acidic cleavage conditions include solutions oftrifluoroacetic acid in a halogenated solvent at room temperature or asin this case, a solution of anhydrous HCl in methanol. Condensation of 5with 2-(trimethylsilyl)ethylp-nitrophenylcarbonate (Fluka ChemicalCompany) afforded the corresponding 2-(trimethylsilyl)ethylcarbamate orTeOC derivative 6 which was hydrolyzed under basic conditions to givethe carboxylic acid 7.

Coupling of the acid 7 with the Wang resin afforded the resin 8 whichwas converted to the resin 9 by treatment with tetrabutylammoniumfluoride (Scheme 2). Reductive aminations were conducted using aldehydesor ketones and borane/pyridine to give the resin-bound N-substitutedderivatives 11. A wide range of aldehydes and ketones were employed inthe reductive amination reaction. For those aldehydes and ketones thatcontained a basic nitrogen atom, such compounds were protected as thereBOC detivatives (e.g., N-Boc-4-piperidinone). Cleavage of the resinusing trifluoroacetic acid gave the desired carboxylic acid derivatives(Formula I; R⁵ is H). Alternatively, cleavage of resin 11 with alcoholssuch as methanol, benzyl alcohol, and the like under acidic conditionsgave esterified compounds of Formula I (R⁵ is alkyl). Under the acidiccleavage conditions, all Boc protecting groups were simultaneouslyremoved to generate the corresponding primary or secondary amine. Thepurity of cleaved products was generally >50% as determined by LCMS andcompounds could be purified to >98% purity by routine HPLC.

In addition to the solid-phase synthesis of compounds of Formula I,standard solution-phase synthesis was also conducted. For example, thesynthetic route employed for the preparation of the carboxylic acid 17bis outlined in Scheme 3. Coupling of the acid 13 [Werner et al. J. Org.Chem., 1996, 61, 587-597] with glycine tert-butyl ester in the presenceof dicyclohexylcarbodiimide and hydroxybenzotriazole afforded thetert-butyl ester 14b which was converted to the triflate 15b usingN-phenyltrifluoromethane sulfonimide. Palladium catalyzed carbonylationof 15b afforded the diester 16b which was converted to the carboxylicacid 17b by acidic cleavage of the ester protecting group. Preparationof the carboxylic acid 17a from 13 was conducted using a similarprocedure as described above. The methyl ester 14a [Werner et al. J.Org. Chem., 1996, 61, 587-597] was converted to the triflate 15a usingN-phenyltrifluoromethane sulfonimide. Palladium catalyzed carbonylationof 15a afforded the diester 16a which was converted to the carboxylicacid 17a by basic cleavage of the methyl esters protecting groups.

Compounds of general formula VIIa were synthesized according to theScheme 4. As an example, oxidation of N-Boc-L-valinol (Aldrich Chemicalcompany) using the Dess Martin periodinane (Lancaster Chemical company)afforded the corresponding N-Boc-L-valinal which was coupled to thepiperidine 5 (see Scheme 1) under reductive amination conditions usingborane/pyridine as reducing agent. The resulting carbamate 18 wasconverted to the primary amine 19 (isolated as its dihydrochloride salt)under acidic conditions. Coupling of 19 with3-(4-hydroxyphenyl)propionic acid (Aldrich Chemical company) using BOPas coupling agent provided the amide 20 which was hydrolyzed under basicconditions to give the carboxylic acid 21. Coupling of 21 with ammoniumchloride using EDCI as coupling agent provided the carboxamide 22.

The derivatives of formula I (R¹ is CONR⁶R⁷) were prepared according tothe Schemes 5-7.

Coupling of the acid 7 (Scheme 1) with the Fmoc-deprotected Rink amideresin afforded the resin 23 which was converted to the resin 24 bytreatment with tetrabutylammonium fluoride (Scheme 5). A wide range ofaldehydes and ketones were employed in the reductive amination reaction.For those aldehydes and ketones that contained a basic nitrogen atom,such compounds were protected as their Boc derivatives (e.g.,N-Boc-4-piperidinone). Cleavage of the resin using trifluoroacetic acidgave the desired carboxamide derivatives (Formula I; R¹ is CONH₂). Underthe acidic cleavage conditions, all Boc protecting groups weresimultaneously removed to generate the corresponding primary orsecondary amine. The purity of cleaved products was generally >50% asdetermined by LCMS and compounds could be purified to >98% purity byroutine HPLC.

In addition to the solid-phase synthesis of compounds of Formula I (R¹is CONR⁶R⁷), standard solution-phase synthesis was also conducted. Forexample, the synthetic route employed for the preparation of thecarboxamides 29 is outlined in Scheme 6. Palladium catalyzed formationof the carboxamides 28 from the triflates 15 (Scheme 3) was conducted inthe presence of carbon monoxide and (TMS)₂NH. Acidic hydrolysis of 28afforded the target compounds 29 as their TFA salt.

The solution-phase synthesis of compounds of Formula I (R¹ is CONR⁶R⁷)may also be conducted as described in Scheme 7. Condensation of 1 withaldehydes or ketones under reductive amination conditions usingborane/pyridine as reducing agent affords the derivatives 30 which areconverted to the triflates 31 using N-phenyltrifluoromethane sulfonimidein a halogenated solvent such as dichloromethane and a tertiary aminebase such as triethylamine. Palladium catalyzed carbonylation of 31provides the methyl esters 32 which are hydrolyzed under basicconditions to give the carboxylic acids 33. Coupling of 33 with variousamines affords the primary, secondary or tertiary amides 34. The primaryalcohols 35 are prepared by reduction of the methyl esters 32 usinglithium aluminum hydride.

The derivatives of formula I (R¹ is —NR⁶R⁷) were prepared according tothe Schemes 8 and 9.

The aniline derivatives 38 were obtained in 3 steps from the triflates15. Palladium catalyzed condensation of benzophenone imine with thetriflates 15 afforded the imines 36 which were converted to the anilinederivatives 37 by treatment with ammonium hydroxide. Acidic or basichydrolysis of 37 afforded the desired target compounds 38. The anilinederivatives 41 could also be obtained in 3 steps from the carboxylicacids 33 (Scheme 9). Curtius rearrangement of 33 afforded theBoc-protected anilines 39 which were deprotected under acidic conditionsto give the anilines 40 (isolated as their dihydrochloride salts).Acylation of 40 with various acyl chloride in the presence oftriethylamine provided the amides 41.

EXAMPLES

Materials: All chemicals were reagent grade and used without furtherpurification. Analytical thin-layer chromatography (TLC) was performedon silica gel glass plates (250 microns) from Analtech and visualized byUV irradiation and iodine. Flash chromatography was conducted withsilica gel (200-400 mesh, 60 Å, Aldrich). Chromatographic elutionsolvent systems are reported as volume:volume ratios. LC-MS data wereobtained using a LC Thermo Finnigan Surveyor-MS Thermo Finnigan AQA ineither positive mode or negative mode. Solvent A: 10 mM ammoniumacetate, pH 4.5; solvent B: acetonitrile; solvent C: methanol; solventD: water; column Waters Xterra C18 MS 2.0×50 mm, detector: PDA λ is220-300 nM. Gradient program (positive mode): t=0.00, 600 μL/min, 99%A-1% B; t=0.30, 600 μL/min, 99% A-1% B; t=5.00, 600 μL/min, 1% A-99% B;t=5.30, 600, μL/min, 1% A-99% B. Gradient program (negative mode):t═0.00, 600 μL/min, 9% A-1% B-90% D; t=0.30, 600 μL/min, 9% A-1% B-90%D; t=5.00, 600 μL/min, 99%B-1% D; t=5.30, 600 μL/min, 99% B-1% D.

Preparation of Key Intermediate 7 (Scheme 1):

4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-tert-butyloxycarbonylpiperidine (2)

To a solution of (+) 4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-1-piperidine(1) (7 g, 0.034 mol, 1 eq) in anhydrous tetrahydrofuran (100 mL) wasadded portion wise tert-butyloxycarbonyl anhydride (8.2 g, 0.0375 mol,1.1 eq). After the addition was complete, triethylamine (5.32 mL, 0.038mol, 1.12 eq) was added and the mixture was stirred for 2 h at roomtemperature. The reaction mixture was poured into diethyl ether (300 mL)and washed consecutively with 1N aqueous HCl (100 mL), water (100 mL)and brine (100 mL). Drying over sodium sulfate followed by removal ofthe solvent under vacuum gave the crude titled product (10.5 g, 100%)used for the next step without further purification.

3(R),4-dimethyl-4(R)-(3-trifluoromethanesulfonyloxyphenyl)-1-tert-butyloxycarbonylpiperidine (3)

To a cold (0° C.) suspension of 2 (10.5 g, 0.034 mol, 1 eq) in anhydrousdichloromethane (100 mL), was added N-triphenyltrifluoromethanesulfonimide (13.51 g, 0.0378 mol, 1.1 eq) followed by addition oftriethylamine (5.75 mL, 0.041 mol, 1.2 eq). The mixture was allowed towarm slowly to room temperature and stirring was continued for 2 h. Themixture was diluted with diethyl ether (200 mL) and washed successivelywith water (100 mL), aqueous 1N NaOH (3×100 mL), water (100 mL), andbrine (100 mL). The organic layer was dried over sodium sulfate andconcentrated under vacuum to furnish the crude product as a yellow oil.Purification by column chromatography (eluent:hexane/ethyl acetate=95:5)afforded the desired product (1.11 g, 74% 2 steps).

4(R)-(3-methoxycarbonylphenyl)-3(R),4-dimethyl-1-tertbutyloxycarbonylpiperidine (4)

To a stirred solution of 3 (10.8 g, 0.024 mol, 1 eq) in a mixture ofmethanol (100 mL) and dimethylsulfoxide (150 mL) was added triethylamine(7.55 mL, 0.054 mol, 2.2 eq). Carbon monoxide gas was bubbled throughthe mixture for 5 minutes. To the mixture was added palladium (II)acetate (0.554 g, 0.0024 mol, 0.1 eq) followed by1,1′-bis(diphenylphosphino)ferrocene (2.73 g, 0.0049 mol, 0.2 eq).Carbon monoxide gas was bubbled through the mixture for 15 minutes andit was then stirred under an atmosphere of carbon monoxide and heated at65° C. overnight. The mixture was cooled to room temperature and pouredinto water (500 mL). The mixture was extracted with ethyl acetate (3×150mL). The combined organic extracts were washed with water (200 mL),brine (200 mL) and dried over sodium sulfate. Evaporation of the solventunder vacuum afforded a dark oil. The crude product was purified bycolumn chromatography (eluent:hexane/ethyl acetate=95:5) affording thetitle compound (6.44 g, 75%).

4(R)-(3-methoxycarbonylphenyl)-3(R),4-dimethyl-1-piperidinehydrochloride (5)

An anhydrous solution of hydrochloric acid in diethyl ether (2Msolution, 55 mL, 0.110 mol, 6 eq) was added to a solution of (4) (6.4 g,0.018 mol, 1 eq) in anhydrous methanol (100 mL). The mixture was heatedto reflux overnight, concentrated and dried under high vacuum.Trituration of the resulting mixture in diethyl ether (100 mL) affordeda white solid which was collected by filtration and washed with diethylether (3×20 mL) (5.11 g, 98%).

4(R)-(3-methoxycarbonylphenyl)-3(R),4-dimethyl-1-(2-trimethylsilylethyloxycarbonyl)piperidine (6)

To a suspension of 5 (1.31 g, 0.0046 mol, 1 eq) in anhydrousacetonitrile (15 mL) was added diisopropylethylamine (1.68 mL, 0.0096mol, 2.1 eq) and 2-(trimethylsilyl)ethyl-p-nitrophenylcarbonate (1.44 g,0.0050 mol, 1.1 eq). The resulting solution was concentrated undervacuum and ethyl acetate (200 mL) was added. The organic layer waswashed with aqueous 1N NaOH (100 mL), aqueous 1N HCl (100 mL), water(100 mL), brine (100 mL), dried over sodium sulfate and concentratedunder vacuum. Purification of the crude product by column chromatography(eluent:hexane/ethyl acetate=95:5) afforded the title compound (1.67 g,92%).

4(R)-(3-carboxyphenyl)-3(R),4-dimethyl-1-(2-trimethylsilylethyloxycarbonyl)piperidine (7)

A solution of lithium hydroxide monohydrate (2.75 g, 0.065 mol, 6 eq) inwater (20 mL) was added drop wise to a cold (0° C.) solution of (6)(4.28 g, 0.0109 mol, 1 eq) in tetrahydrofuran (40 mL). The mixture wasallowed to warm to room temperature and stirring was continued for 5days. A 1N aqueous HCl solution (100 mL) was added to the mixture whichwas extracted with ethyl acetate (3×100 mL). The combined organicextracts were washed with water (100 mL), brine (100 mL) and dried oversodium sulfate. Evaporation of the solvent afforded the desired compound(4.0 g, 97%).

Preparation of Resin 8

To a suspension of the Wang resin (PL-Wang, 150-300 μM, 1.7 mmol/g, 1.6g, 0.0027 mol, 1 eq) (Scheme 2) in a mixturedichloromethane/dimethylformamide 9:1 (30 mL) was added consecutively4(R)-(3-carboxyphenyl)-3(R),4-dimethyl-1-(2-trimethylsilylethyloxycarbonyl)piperidine (7) (2.55 g, 0.0067 mol, 2.5 eq), 4-dimethylaminopyridine(DMAP) (0.370 g, 0.0030 mol, 1.12 eq) and diisopropylcarbodiimide (1.27mL, 0.008 mol, 3 eq). The mixture was shaken for 7 h at roomtemperature. The resin was then drained, washed consecutively withdimethylformamide (5×), dimethylformamide/water (9:1) (5×),dimethylformamide (5×), methanol (5×), dichloromethane (5×),diethylether (5×) and dried under vacuum. Qualitative analysis of theresin was performed by single bead FT-IR. γ(C═O) ester :1715 cm⁻¹;γ(C═O) carbamate: 1696 cm⁻¹

Preparation of Resin 9

The resin 8 (estimated loading: 80%; 1.36 mmol/g, 2.67 g, 0.0036 mol)was swelled in anhydrous tetrahydrofuran (30 mL), treated with a 1Msolution of tetrabutylammonium fluoride in tetrahydrofuran (18.15 mL,0.018 mol, 5 eq) and shaken for 16 h at room temperature. The resin wasdrained, washed with THF (5×), treated with THF/water 1:1 (30 mL) andshaken at room temperature for 2 hours. The resin was drained andfurther washed consecutively with dimethylformamide (5×),dimethylformamide/water (9:1) (5×), dimethylformamide (5×), methanol(5×), dichloromethane (5×), diethylether (5×). Qualitative analysis ofthe TeoC deprotection was conducted using single bead FT-IR.

General Procedure for Reductive Amination on Solid Support

Preparation of Resin 11

A 1 N solution of aldehyde or ketone (130 μL, 0.00017 mol, 14 eq) in amixture N-methylpyrrolidinone/ethanol 3:1 was added to the resin 9 (10mg, estimated loading: 1.22 mmol/g, 0.0000122 mol, 1 eq) and the mixturewas shaken overnight at room temperature (imine formation). A 8 Nsolution of borane in pyridine (210 μL, 0.00017 mol, 14 eq) was thenadded to the mixture which was shaken for 4 days at room temperature.The resin was then drained, washed consecutively with dimethylformamide(5×), dimethylformamide/water (9:1) (5×), dimethylformamide (5×),methanol (5×), dichloromethane (5×), diethylether (5×), and dried undervacuum. For Example 1, cyclohexanone was used as the ketone reagent.

General Procedure for Cleavage of Resin 11

The resin 11 (10 mg) was shaken in a mixture trifluoroacticacid/dichloromethane (1:1) (300 μL) at room temperature for 20 min. thefiltrate was collected and the resin was further washed withdichloromethane (300 μL) and acetonitrile (300 μL). Evaporation of thefiltrate afforded the desired compound.

Example 1 Preparation of3-(1-Cyclohexyl-3R,4R-dimethyl-piperidin-4-yl)-benzoic acid (12)

The title compound 12 was synthesized using the general experimentalprotocol outlined previously using cyclohexanone as the ketone reagent.For Example 1, R₄ is cyclohexyl; Mass spectral analysis: m/z=316 (M+H)⁺

Example 2 Preparation of (3-(3R,4R-Dimethyl-piperidin-4-yl)-benzoic acid(10)

The resin 9 (10 mg) was shaken in a mixture trifluoroaceticacid/dichloromethane (1:1) (300 μL) at room temperature for 20 minutes.The filtrate was collected and the resin was further washed withdichloromethane (300 μL) and acetonitrile (300 μL). Evaporation of thefiltrate afforded the desired title compound; For Example 2, R⁴ is H;Mass spectral analysis: m/z=234 (M+H)⁺

Using procedures described above for Example 1, Examples 3-26 wereprepared (Table 1).

Example 273-[1-(2S-Carboxy-3-phenyl-propyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoicacid (17a)

To a cold (0° C.) solution of methyl(αR,3R,4S)-4-(3-hydroxyphenyl)-3,4-dimethyl-α-(phenylmethyl)-1-piperidinepropanoatehydrochloride (14a) (1.5 g, 0.003 mmol, 1 eq) in anhydrousdichloromethane (15 mL) was added triethylamine (1.2 mL, 0.0086 mmol,2.4 eq) followed by N-triphenyltrifluoromethane sulfonimide (1.41 g,0.0039 mmol, 1.1 eq). The mixture was allowed to warm slowly to roomtemperature and stirring was continued for 2 h. The mixture was dilutedwith diethyl ether (200 mL) and washed successively with water (100 mL),aqueous 1N NaOH (3×100 mL), water (100 mL), and brine (100 mL). Theorganic layer was dried over sodium sulfate and concentrated undervacuum to furnish the crude product as a yellow oil. Purification bycolumn chromatography (eluent:hexane/ethyl acetate=95:5) afforded thedesired product 15a (1.72 g, 93%); Mass spectral analysis: m/z=514(M+H)⁺.

To a stirred solution of 15a (1.72 g, 0.0033 mol, 1 eq) in a mixture ofmethanol (15 mL) and dimethylsulfoxide (20 mL) was added triethylamine(1.03 mL, 0.0073 mol, 2.2 eq). Carbon monoxide gas was bubbled throughthe mixture for 5 minutes. To the mixture was added palladium (II)acetate (0.075 g, 0.00033 mol, 0.1 eq) followed by1,1′-bis(diphenylphosphino)ferrocene (0.371 g, 0.00067 mol, 0.2 eq).Carbon monoxide gas was bubbled through the mixture for 15 minutes andit was then stirred under an atmosphere of carbon monoxide and heated at65° C. overnight. The mixture was cooled to room temperature and pouredinto water (100 mL). The mixture was extracted with ethyl acetate (3×50mL). The combined organic extracts were washed with water (100 mL),brine (100 mL) and dried over sodium sulfate. Evaporation of the solventunder vacuum afforded an oil. The crude product was purified by columnchromatography (eluent:hexane/ethyl acetate=95:5) affording the desiredcompound 16a (0.720 g, 51%); Mass spectral analysis: m/z=424 (M+H)⁺.

A solution of aqueous 2N sodium hydroxide (2.55 mL, 0.00509 mol, 6 eq)was added drop wise to a cold (0° C.) solution of 16a (0.360 g, 0.00084mol, 1 eq) in tetrahydrofuran (10 mL). The mixture was allowed to warmto room temperature and stirring was continued for 5 hours. A solutionof lithium hydroxide monohydrate (0.213 g, 0.0050 mol, 6 eq) in water (5mL) was added to the mixture [methanol (3 mL) was added forsolubilization] and stirring was continued for 12 hours. A 12N aqueousHCl solution (0.8 mL) was added to neutralize the mixture which wasconcentrated under vacuum. The precipitate was collected by filtrationand washed with diethylether. The desired compound 17a (Example 27) wasobtained as a white solid (0.2 g, 64%); Mass spectral analysis: m/z =396(M+H)⁺

Example 28 Preparation of[[2(R)-[[4(R)-(3-carboxyphenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]aceticAcid (17b)

To a suspension of(αR,3R,4S)-4-(3-hydroxyphenyl)-3,4-dimethyl-α-(phenylmethyl)-1-piperidinepropanoicacid (13) (4 g, 0.88 mmol), glycine tert-butyl ester hydrochloride (2 g,11.96 mmol, 1.1 eq) and hydroxybenzotriazole (1.62 g, 11.96 mmol, 1.1eq) in anhydrous tetrahydrofuran (35 mL) was added under nitrogentriethylamine (1.67 mL, 11.96 mmol, 1.1 eq) followed by a solution ofdicyclohexylcarbodiimide (2.47 g, 11.96 mmol, 1.1 eq) in anhydroustetrahydrofuran (15 mL) (Scheme 3). The reaction mixture was stirred atroom temperature for 60 h, cooled to 0° C. for 30 minutes and filtered.The filtrate was concentrated under vacuum and ethyl acetate (100 mL)was added. The solution was washed with and saturated aqueous solutionof sodium carbonate (100 mL) and brine (100 mL). The organic layer wasdried over sodium sulfate, filtered and placed in a fridge overnight toallow residual traces of dicyclohexylurea to precipitate. The suspensionwas then filtered and the filtrate was concentrated to give compound 14bas yellow foam (6 g, 100%). Mass spectral analysis: m/z=481 (M+H)⁺

To a solution of 14b (0.1 g, 0.208 mmol, 1 eq) in anhydrousdichloromethane (1 mL) was added triethylamine (48 μL, 0.345 mmol, 1.66eq) followed by drop wise addition of a solution ofN-triphenyltrifluoromethane sulfonimide (0.111 g, 0.312 mmol, 1.5 eq) inanhydrous dichloromethane (0.1 mL) at room temperature under argon. Thereaction mixture was allowed to stir at room temperature overnight. Thereaction mixture was washed with aqueous 1N NaOH solution (2 mL) andconcentrated under vacuum. The residue was then resuspended indichloromethane (5 mL) and aqueous 1N NaOH solution (2 mL) and stirredat room temperature for 30 minutes. The organic layer was separated andthe aqueous phase was extracted with dichloromethane (3×2.5 mL). Thecombined organic extracts were washed with aqueous 1N NaOH solution (2mL) and dried over sodium sulfate. The mixture was filtrated and thefiltrate was concentrated to afford 15b as a red colored clear oil.(0.133 g, 100%). Mass spectral analysis: m/z=613 (M+H)⁺

A solution of (15b) (0.5 g, 0.816 mmol, 1 eq), palladium acetate (36.2mg, 20mol %, 0.163 mmol), diphenylphoshinopropane (65.2 mg, 20 mol %,0.163 mmol), triethylamine (284 μL, 2.026 mmol, 2.5 eq) in anhydrousdimethylformamide (10 mL) and methanol (6 mL) was purged with CO(g) for10 minutes and the reaction mixture was stirred for 16 hours at 70° C.under a carbon monoxide atmosphere (Scheme 3). The mixture wasconcentrated under vacuum and purified by column chromatography(eluent:dichloromethane/methanol=98:2). (0.421 g, 99%). For 16b massspectral analysis: m/z=523 (M+H)⁺

To a solution of 16b (0.350 g, 0.670 mmol, 1 eq) in tetrahydrofuran (50mL) was added an aqueous 1N NaOH solution (50 mL) and the reactionmixture was stirred at room temperature for 16 h. The reaction mixturewas concentrated and the pH was adjusted to 4. The mixture was extractedwith chloroform/isopropanol (3:1, 150 mL). The organic extract was driedover sodium sulfate and concentrated to afford the title compound 17b(Example 28) (0.142 g, 50%). Mass spectral analysis: m/z=453 (M+H))⁺

Example 29 Preparation of3-(1-{2-[3-(4-Hydroxyphenyl)-propionylamino]-3-methyl-butyl}-3R,4R-dimethyl-piperidin-4-yl)benzoicacid (21)

To a solution of Dess-Martin periodinane (3.12 g, 0.0073 mol, 1.5 eq) indichloromethane (25 mL) was added a solution of N-Boc-L-valinol (1 g,0.0049 mol, 1 eq) in dichloromethane (25 mL). The reaction mixture wasstirred at room temperature for 3 h and was diluted with diethyl ether(50 mL). The mixture was poured into an aqueous saturated solution ofsodium bicarbonate (100 mL) containing sodium thiosulfate (8.16 g, 10.5eq). The mixture was stirred for 30 min and the layers were separated.The ether layer was washed with an aqueous saturated solution of sodiumbicarbonate (50 mL), water (50 mL), dried (sodium sulfate) and filtered.The filtrate was concentrated to give the crude(1-formyl-2-methyl-propyl)-carbamic acid tert-butyl ester used for thenext step without further purification.

An 8 M solution of borane in pyridine (1.43 mL, 0.0114 mol, 2.75 eq) wasadded to a solution of (1-formyl-2-methyl-propyl)-carbamic acidtert-butyl ester (N-Boc-L-valinal) (2.3 g, 0.01142 mol, 2.75 eq),4(R)-(3-methoxycarbonylphenyl)-3(R),4-dimethyl-1-piperidinehydrochloride (5) (1.18 g, 0.00415 mol, 1 eq) and triethylamine (0.64mL, 0.0045 mol, 1.1 eq) in methanol (15 mL). The mixture was stirred for6 h at room temperature and concentrated under vacuum. Purification ofthe crude product by column chromatography(eluent:dichloromethane/methanol=98:2) afforded the desired compound 18(0.280 g, 15%); Mass spectral analysis: m/z=433 (M+H)⁺

An anhydrous solution of hydrochloric acid in diethyl ether (2Msolution, 1.94 mL, 0.0038 mol, 6 eq) was added to a solution of 18(0.280 g, 0.00064 mol, 1 eq) in anhydrous methanol (20 mL). The mixturewas heated to reflux overnight, concentrated and dried under highvacuum. Trituration of the resulting mixture in diethyl ether (10 mL)afforded a white solid (19) which was collected by filtration and washedwith diethyl ether (0.250 g, 95%); Mass spectral analysis, m/z=333(M+H)⁺

To a suspension of 19 (0.420 g, 0.0010 mol, 1 eq), BOP reagent (0.458 g,0.0010 mol, 1 eq) and triethylamine (0.75 mL, 0.0054 mol, 5.2 eq) intetrahydrofuram (30 mL) was added 3-(4-hydroxyphenyl)propionic acid(0.206 g, 0.0012 mol, 1.2 eq) and the mixture was stirred for 3 hours atroom temperature. Diethyl ether (100 mL) was added and the solution waspoured into an aqueous saturated solution of sodium bicarbonate (50 mL).The organic layer was separated, washed with water, dried (sodiumsulfate),filtered and concentrated. The crude product was purified bycolumn chromatography (eluent:dichloromethane/methanol=95:5) affordingthe desired compound 20 (0.300 g, 60%); Mass spectral analysis: m/z=481(M+H)⁺

A solution of lithium hydroxide monohydrate (0.078 g, 0.0018 mol, 6 eq)in water (1 mL) was added to a cold (0° C.) solution of 20 (0.150 g,0.00031 mol, 1 eq) in tetrahydrofuran (10 mL). Methanol (3 mL) was addedfor solubilization. The mixture was allowed to warm to room temperatureand stirring was continued for 12 hours. A 12N aqueous HCl solution wasadded to neutralize the mixture which was concentrated under vacuum. Theprecipitate was collected by filtration and washed with diethylether.The desired compound 21 (Example 29) was obtained as a white solid(0.090 g, 62%); Mass spectral analysis: m/z=467 (M+H)⁺

Preparation of Resin 23

A solution dimethylformamide/piperidine 75:25 (3 mL) was added to therink amide resin (1.06 mmol/g, 0.185 g, 0.00057 mol, 1 eq) and thesuspension was mixed at room temperature for 1 hour (Scheme 5). Theresin was then drained, washed consecutively with dimethylformamide(5×), dimethylformamide/water (9:1) (5×), dimethylformamide (5×),methanol (5×), dichloromethane (5×), diethylether (5×) and dried undervacuum. To a suspension of the resulting resin in a mixturedichloromethane/dimethylformamide 9:1 (5 mL) was added consecutivelydiisopropylethylamine (0.24 mL, 0.00143 mol, 2.5 eq),4(R)-(3-carboxyphenyl)-3(R),4-dimethyl-1-(2-trimethylsilylethyloxycarbonyl)piperidine (7) (0.54 g, 0.00143 mol, 2.5 eq), 1-hydroxybenzotriazole(0.015 g, 0.0001 mol, 0.2 eq) and HATU (0.545 g, 0.00143 mol, 2.5 eq).The mixture was shaken overnight at room temperature. The resin was thendrained, washed consecutively with dimethylformamide (5×),dimethylformamide/water (9:1) (5×), dimethylformamide (5×), methanol(5×), dichloromethane (5×), diethylether (5×) and dried under vacuum.

Preparation of Resin 24

The resin 23 (estimated loading: 100%; 1.06 mmol/g, 4 g, 4.24 mmol) wasswelled in anhydrous tetrahydrofuran (30 mL), treated with a 1 Msolution of tetrabutylammonium fluoride in tetrahydrofuran (21.2 mL,21.2 mmol, 5 eq) and shaken for 16 hours at room temperature. The resinwas drained, washed with THF (5×), then treated with THF/water 1:1 (60mL) and shaken at room temperature for 2 hours. The resin was drainedand further washed consecutively with dimethylformamide (5×),dimethylformamide/water (9:1) (5×), dimethylformamide (5×), methanol(5×), dichloromethane (5×), diethylether (5×).

General Procedure for Reductive Amination on Solid Support

Preparation of Resin 26

A 5 N solution of aldehyde or ketone (0.16 mL, 0.000848 mol, 10 eq) inN-methylpyrrolidinone was added to a suspension of the resin 24 (80 mg,estimated loading: 1.06 mmol/g, 0.0000848 mol, 1 eq) in a mixtureN-methylpyrrolidinone/ethanol 3:1 (2 mL) and the mixture was shaken for1 h at room temperature (imine formation). A 8N solution of borane inpyridine (0.10 mL, 0.000848 mol, 10 eq) was then added to the mixturewhich was shaken for 4 days at room temperature. The resin was thendrained, washed consecutively with dimethylformamide (5×),dimethylformamide/water (9:1) (5×), dimethylformamide (5×), methanol(5×), dichloromethane (5×), diethylether (5×), and dried under vacuum.For Example 30, cyclohexanone was used as the ketone reagent.

General Procedure for Cleavage of Resin 26

The resin 26 (30 mg) was shaken in a mixture trifluoroaceticacid/dichloromethane (1:1) (300 μL) at room temperature for 20 minutes.The filtrate was collected and the resin was further washed withdichloromethane (300 μL) and acetonitrile (300 μL). Evaporation of thefiltrate afforded the desired compound.

Example 30 Preparation of3-(1-Cyclohexyl-3R,4R-dimethyl-piperidin-4-yl)-benzamide (27)

The title compound 27 was synthesized using the general experimentalprotocol for reductive amination on a solid support outlined previouslyusing cyclohexanone as the ketone reagent. Example 30: R₄ is cyclohexyl;Mass spectral analysis: m/z=315 (M+H)⁺

Example 31 Preparation of 3-(3R,4R-Dimethyl-piperidin-4-yl)-benzamide(25)

The resin 24 (10 mg) was shaken in a mixture trifluoroacticacid/dichloromethane (1:1) (300 μL) at room temperature for 20 minutes.The filtrate was collected and the resin was further washed withdichloromethane (300 μL) and acetonitrile (300 μL). Evaporation of thefiltrate afforded the desired title compound. For Example 31, R₄ is H;Mass spectral analysis: m/z=233 (M+H)⁺

Using procedures described above for Example 30, Examples 32-57 wereprepared (Table 2).

Example 58 Preparation of[[2(R)-[[4(R)-(3-amidophenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]aceticAcid (29b)

A stirred solution of 15b (0.5 g, 0.816 mmol, 1 eq), palladium chloride(9 mg, 6 mol %, 48.96 μmol), diphenylphosphinopropane (39 mg, 12 mol %,97.9 μmol) and HN(TMS)₂ (0.69 mL, 3.264 mmol, 4 eq) was purged withCO(g) for 5 minutes, then stirred under an atmosphere of CO(g) for 1hour at 80° C. After this time was added palladium acetate (18 mg, 10mol %, 0.0816 mmol) and diphenylphosphinopropane (65 mg, 0.163 mmol).This mixture was purged with CO(g) for 10 minutes, then stirred under anatmosphere of CO(g) for 4 hours at 85-90° C. The reaction mixture wasconcentrated under vacuum and partitioned between dichloromethane (50mL) and water (50 mL). The aqueous layer was extracted withdichloromethane (2×50 mL). The combined organic extracts were washedwith brine (50 mL), dried over sodium sulfate and concentrated. Thecrude product was purified by column chromatography(eluent:dichloromethane/methanol=97.5:2.5) affording compound 28b as ayellow foamy solid. (0.170 g, 41%); Mass spectral analysis: m/z 508(M+H)⁺

A solution of 28b (0.170 g, 0.335 mmol, 1 eq) in 4N HCl in dioxane (7.5mL) was stirred at room temperature for 2.5 hours. The solvent wasremoved under vacuum affording a yellow crystalline solid. The crudeproduct was purified by preparative HPLC (methanol/water/TFA) affordingthe title compound 29b (Example 58) as the TFA salt (0.098 g, 55%); Massspectral analysis: m/z=424 (M+H)⁺

Example 59 Preparation of3-(1-{2-[3-(4-Hydroxyphenyl)-propionylamino]-3-methyl-butyl}-3R,4R-dimethyl-piperidin-4-yl)benzamide(22)

To a suspension of the acid 21 (0.190 g, 0.00040 mol, 1 eq) andtriethylamine (0.18 mL, 0.0013 mol, 3.2 eq) in dimethylformamide (10 mL)was added ammonium chloride (0.109 g, 0.0020 mol, 5 eq),hydroxybenzotriazole (0.066 g, 0.00048 mol, 1.2 eq) and EDCI (0.109 g,0.00057 mol, 1.4 eq) and the mixture was stirred for 24 hours at roomtemperature. The mixture was poured into an aqueous saturated solutionof sodium bicarbonate (50 mL) and extracted with ethyl acetate. Theorganic layer was separated, washed with water, dried (sodium sulfate),filtered and concentrated. The crude product was purified by columnchromatography (eluent:dichloromethane/methanol=95:5) affording thedesired compound 22 (Example 59) (0.110 g, 58%); Mass spectral analysis:m/z =466, (M+H)⁺

Example 60 Preparation of[[2(R)-[[4(R)-(3-aminophenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]aceticAcid (38b)

A mixture of 15b (0.250 g, 0.408 mmol, 1 eq), diphenylphosphinopropane(34 mg, 15 mol %, 61.20 μmol), Pd₂(dba)₃ (18.7 mg, 5 mol %, 20.4 μmol),sodium tert-butoxide (86.3 mg, 0.898 mmol, 2.2 eq), benzophenoneimine(82.2 μL, 0.489 mmol, 1.2 eq) in anhydrous toluene was degassed usingargon and was then heated to 80° C. for 17 hours. The reaction mixturewas cooled to room temperature and quenched by addition of an aqueoussaturated solution of ammonium chloride (25 mL). The organic layer wasseparated and the aqueous layer was further extracted withdichloromethane (2×25 mL). The combined organic extracts were washedwith brine (25 mL), dried over sodium sulfate and concentrated.Purification of the crude product by column chromatography(eluent:dichloromethane/methanol=1:1) afforded the compound 36b as a tansolid (0.136 g, 52%).

A mixture of 36b (0.136 g, 0.211 mmol, 1 eq), hydroxylaminehydrochloride (30 mg, 0.425 mmol, 2 eq), sodium acetate (87 mg, 1.056mmol, 5 eq) and methanol (2.5 mL) was stirred at room temperature for 45minutes under argon. The solvent was removed in vacuo and the reactionmixture was extracted with dichloromethane (20 mL). The aqueous layerwas further extracted with dichloromethane (2×20 mL). The combinedorganic extracts were washed with an aqueous saturated solution ofsodium bicarbonate (20 mL), dried over sodium sulfate and concentrated.Purification of the crude product by column chromatography(eluent:dichloromethane/methanol=97.5:2.5) afforded the desired product37b (62 mg, 61%); Mass spectral analysis: m/z=480 (M+H)⁺

A solution of 37b (0.170 g, 0.335 mmol, 1 eq) in 4N HCl in dioxane (7.5mL) was stirred at room temperature for 1 h 30 min. The solvent wasremoved under vacuum. The crude product was purified by preparative HPLC(acetonitrile/water/TFA) affording the title compound 38b (Example 60)as the diTFA salt (0.100 g, 74%); Mass spectral analysis: m/z=424 (M+H)⁺

Biological Assays

The potencies of the compounds were determined by testing the ability ofa range of concentrations of each compound to inhibit the binding of thenon-selective opioid antagonist, [³H]diprenorphine, to the cloned humanμ, κ, and δ opioid receptors, expressed in separate cell lines. IC₅₀values were obtained by nonlinear analysis of the data using GraphPadPrism version 3.00 for Windows (GraphPad Software, San Diego). K_(i)values were obtained by Cheng-Prusoff corrections of IC₅₀ values.

Receptor Binding (In Vitro Assay)

The receptor binding method (DeHaven and DeHaven-Hudkins, 1998) was amodification of the method of Raynor et al. (1994). After dilution inbuffer A and homogenization as before, membrane proteins (10-80 μg) in250 μL were added to mixtures containing test compound and[³H]diprenorphine (0.5 to 1.0 nM, 40,000 to 50,000 dpm) in 250 μL ofbuffer A in 96-well deep-well polystyrene titer plates (Beckman). Afterincubation at room temperature for one hour, the samples were filteredthrough GF/B filters that had been presoaked in a solution of 0.5% (w/v)polyethylenimine and 0.1% (w/v) bovine serum albumin in water. Thefilters were rinsed 4 times with 1 mL of cold 50 mM Tris HCl, pH 7.8 andradioactivity remaining on the filters determined by scintillationspectroscopy. Nonspecific binding was determined by the minimum valuesof the titration curves and was confirmed by separate assay wellscontaining 10 μM naloxone. K_(i) values were determined by Cheng-Prusoffcorrections of IC₅₀ values derived from nonlinear regression fits of 12point titration curves using GraphPad Prisms® version 3.00 for Windows(GraphPad Software, San Diego, Calif.).

To determine the equilibrium dissociation constant for the inhibitors(K_(i)), radioligand bound (cpm) in the presence of variousconcentrations of test compounds was measured. The concentration to givehalf-maximal inhibition (EC₅₀) of radioligand binding was determinedfrom a best nonlinear regression fit to the following equation,

$Y = {{Bottom} + \frac{\left( {{Top} - {Bottom}} \right)}{1 + 10^{X - {LogEC50}}}}$where Y is the amount of radioligand bound at each concentration of testcompound, Bottom is the calculated amount of radioligand bound in thepresence of an infinite concentration of test compound, Top is thecalculated amount of radioligand bound in the absence of test compound,X is the logarithm of the concentration of test compound, and LogEC50 isthe log of the concentration of test compound where the amount ofradioligand bound is half-way between Top and Bottom. The nonlinearregression fit was performed using the program Prism® (GraphPadSoftware, San Diego, Calif.). The K_(i) values were then determined fromthe EC₅₀ values by the following equation,

$K_{i} = \frac{{EC}_{50}}{1 + \frac{\lbrack{ligand}\rbrack}{K_{d}}}$where [ligand] is the concentration of radioligand and K_(d) is theequilibrium dissociation constant for the radioligand.

The potencies of the antagonists were assessed by their abilities toinhibit agonist-stimulated [³⁵S]GTPγS binding to membranes containingthe cloned human μ, κ, or δ opioid receptors. The agonists used wereloperamide for the μ opioid receptor, U50488H for the κ opioid receptor,and BW373U86 for the δ opioid receptor.

To determine the IC₅₀ value, which was the concentration to givehalf-maximal inhibition of agonist-stimulated [³⁵S]GTPγS binding, theamount of [³⁵S]GTPγS bound in the presence of a fixed concentration ofagonist and various concentrations of antagonist was measured. The fixedconcentration of agonist was the EC₈₀ for the agonist, which was theconcentration to give 80% of the relative maximum stimulation of[³⁵S]GTPγS binding. The IC₅₀ value was determined from a best nonlinearregression fit of the data to the following equation,

$Y = {{Bottom} + \frac{\left( {{Top} - {Bottom}} \right)}{1 + 10^{X - {LogIC50}}}}$where Y is the amount of [³⁵S]GTPγS bound at each concentration ofantagonist, Bottom is the calculated amount of [³⁵S]GTPγS bound in thepresence of an infinite concentration of antagonist, Top is thecalculated amount of [³⁵S]GTPγS bound in the absence of addedantagonist, X is the logarithm of the concentration of antagonist, andLogIC₅₀ is the logarithm of the concentration of antagonist where theamount of [³⁵S]GTPγS bound is halfway between Bottom and Top. Thenonlinear regression fit was performed using GraphPad Prisms® version3.00 for Windows (GraphPad Software, San Diego, Calif.).

The compounds described in Table 1-3 (examples 1-60) were tested fortheir affinity towards the mu, delta and kappa opioid receptors. All ofthese compounds bind with affinity less than 100 μM to the μ, δ and κopioid receptors. These compounds displayed various degree ofselectivity mu vs delta, mu vs kappa and kappa vs delta The activity ofselected ligands was also evaluated in vitro. Numerous compounds werefound to be pure antagonist at the μ opioid receptor (no agonistactivity detectable at concentration >10 μM). Example 28 (Table 1) bindsto the μ, δ and κ opioid receptors with affinity (expressed as K_(i)value) of 19 nM, 1333 nM and 2000 nM, respectively. Furthermore, Example28 displayed potent in vitro antagonist activity (IC₅₀=3.4 nM). Example58 (Table 2) binds to the μ, δ and κ opioid receptors with affinity(expressed as K_(i) value) of 2.6 nM, 85 nM and 1080 nM, respectively.Furthermore, the compound 58 displayed potent μ in vitro antagonistactivity (IC₅₀=3.0 nM).

Mouse Gastrointestinal Transit (GIT) Assay (In Vivo Assay)

Male Swiss-Webster mice (25-30 g) obtained from Ace Animals (Boyertown,Pa.) were used for all experiments. Mice were housed 4/cage inpolycarbonate cages with food and water available ad libitum. Mice wereon a 12 hours light:dark schedule with lights on at 6:30 a.m. Allexperiments were performed during the light cycle. Mice were fasted thenight before the experiment, with water available ad libitum.

Mice were administered vehicle (10% DMSO:20% Cremophor EL:70% saline) ortest compound (10 mg/kg) orally 2 or 6 hours before determination ofGIT. Compounds were administered in a volume of 0.1 ml/10 g of bodyweight. Morphine (3 mg/kg) or vehicle (0.9% saline) was administereds.c. 35 min prior to determination of GIT. Ten minutes after themorphine treatment, mice were administered 0.2 ml of a charcoal mealorally. The charcoal meal consisted of a slurry of charcoal, flour, andwater in the following ratio (1:2:8, w:w:v). Twenty-five minutes afterreceiving the charcoal meal, the mice were euthanized with CO₂ and GITdetermined.

GIT is expressed as the % GIT by the following formula:

$\frac{\left( {{distance}\mspace{14mu}{to}\mspace{14mu}{leading}\mspace{14mu}{edge}\mspace{14mu}{of}\mspace{14mu}{charcoal}\mspace{14mu}{meal}\mspace{14mu}({cm})} \right)}{\left( {{total}\mspace{14mu}{length}\mspace{14mu}{of}\mspace{14mu}{the}\mspace{14mu}{small}\mspace{14mu}{intestine}\mspace{14mu}({cm})} \right).} \times 100$For each compound a % Antagonism (% A) value was determined for the 2and 6 hr antagonist pretreatment. Using the mean % GIT for eachtreatment group, % A was calculated using the following formula:

$1 - {\frac{\begin{matrix}\left( \left( {{{mean}\mspace{14mu}{vehicle}\mspace{14mu}{response}} -} \right. \right. \\\left. \left. {{{mean}\mspace{14mu}{antagonist}} + {{morphine}\mspace{14mu}{response}}} \right) \right)\end{matrix}}{\left( {{{mean}\mspace{14mu}{vehicle}\mspace{14mu}{response}} - {{mean}\mspace{14mu}{morphine}\mspace{14mu}{response}}} \right)} \times 100}$

The antagonist activity of selected compounds was evaluated using theMouse Gastrointestinal Transit (GIT) Assay (in vivo assay). Numerouscompounds tested were found to have antagonist activity in this assayranging from 20% to 100%. The Example 28 (10 mg/kg; p.o.) displays 86%antagonism at 2 h and 71% at 6 h. The Example 58 (10 mg/kg; p.o.)displays 92% antagonism at 2 h and 61% at 6 h.

TABLE 1 DERIVATIVES OF FORMULA I (R¹ is CO₂H) Example Structure Name[M + H]⁺  1

3-(1-Cyclohexyl-3R,4R-dimethyl-piperidin-4-yl)-benzoic acid 316  2

3-(3R,4R-Dimethyl-piperidin-4-yl)-benzoicacid 234  3

3-[1-(3-Benzyloxy-benzyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoic acid430  4

3-(1-Biphenyl-4-ylmethyl-3R,4R-dimethyl-piperidin-4-yl)-benzoic acid 400 5

3-[3R,4R-Dimethyl-1-(3-phenoxy-benzyl)-piperidin-4-yl]-benzoic acid 416 6

3-[1-(4-Dimethylamino-benzyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoicacid 367  7

3-[3R,4R-Dimethyl-1-(2-pyridin-4-yl-benzyl)-piperidin-4-yl]-benzoic acid401  8

3-{1-[4-(4-Fluoro-phenoxy)-benzyl]-3R,4R-dimethyl-piperidin-4-yl}-benzoicacid 434  9

3-[3R,4R-Dimethyl-1-(4-pyrimidin-5-yl-benzyl)-piperidin-4-yl]-benzoicacid 402 10

3-[3R,4R-Dimethyl-1-(4-pyridin-3-yl-benzyl)-piperidin-4-yl]-benzoic acid401 11

3-[3R,4R-Dimethyl-1-(4-pyridin-4-yl-benzyl)-piperidin-4-yl]-benzoic acid401 12

3-{1-[4-(3-Dimethylamino-propoxy)-benzyl]-3R,4R-dimethyl-piperidin-4-yl}-benzoicacid 425 13

3-{1-[4-(4-Fluoro-benzyloxy)-benzyl]-3R,4R-dimethyl-piperidin-4-yl}-benzoicacid448 14

3-[1-(4′-Fluoro-biphenyl-4-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoicacid418 15

3-[1-(4′-Fluoro-biphenyl-3-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoicacid418 16

3-[1-(2-Ethoxycarbonyl-cyclopropylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoicacid 360 17

3-[1-(1-Benzenesulfonyl-1H-pyrrol-2-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoicacid 453 18

3-{3R,4R-Dimethyl-1-[1-(2-morpholin-4-yl-ethyl)-1H-pyrrol-2-ylmethyl]-piperidin-4-yl}-benzoicacid 424 19

3-[1-(1-Isoxazol-3-yl-1H-pyrrol-2-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoicacid 380 20

3-(1-Bicyclo[2.2.1]hept-5-en-2-ylmethyl-3R,4R-dimethyl-piperidin-4-yl)-benzoicacid340 21

3-[3R,4R-Dimethyl-1-(4-methylsulfanyl-benzyl)-piperidin-4-yl]-benzoicacid 370 22

3-(3R,4R,1′-Trimethyl-[1,4′]bipiperidinyl-4-yl)-benzoic acid 331 23

3-(1′-Benzyl-3R,4R,3′-trimethyl-[1,4′]bipiperidinyl-4-yl)-benzoic acid421 24

3-(3R,4R-Dimethyl-[1,4′]bipiperidinyl-4-yl)-benzoic acid 317 25

3-[1-(1-Benzyl-pyrrolidin-3-yl)-3R,4R-dimethyl-piperidin-4-yl]-benzoicacid 393 26

3-(1-Cyclopentyl-3R,4R-dimethyl-piperidin-4-yl)-benzoic acid 302 27

3-[1-(2S-Carboxy-3-phenyl-propyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoicacid396 28

[[2(R)-[[4(R)-(3-carboxyphenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]aceticAcid 453 29

3-(1-{2-[3-(4-Hydroxyphenyl)-propionylamino]-3-methyl-butyl}-3R,4R-dimethyl-piperidin-4-yl)benzoicacid 467

TABLE 2 DERIVATIVES OF FORMULA I (R¹ is CONH₂) Example Structure Name[M + H]⁺ 30

3-(1-Cyclohexyl-3R,4R-dimethyl-piperidin-4-yl)-benzamide 315 31

3-(3R,4R-Dimethyl-piperidin-4-yl)-benzamide 233 32

3-[1-(3-Benzyloxy-benzyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide 42933

3-(1-Biphenyl-4-ylmethyl-3R,4R-dimethyl-piperidin-4-yl)-benzamide 399 34

3-[3R,4R-Dimethyl-1-(3-phenoxy-benzyl)-piperidin-4-yl]-benzamide 415 35

3-[1-(4-Dimethylamino-benzyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide366 36

3-[3R,4R-Dimethyl-1-(2-pyridin-4-yl-benzyl)-piperidin-4-yl]-benzamide400 37

3-{1-[4-(4-Fluoro-phenoxy)-benzyl]-3R,4R-dimethyl-piperidin-4-yl}-benzamide433 38

3-[3R,4R-Dimethyl-1-(4-pyrimidin-5-yl-benzyl)-piperidin-4-yl]-benzamide401 39

3-[3R,4R-Dimethyl-1-(4-pyridin-3-yl-benzyl)-piperidin-4-yl]-benzamide400 40

3-[3R,4R-Dimethyl-1-(4-pyridin-4-yl-benzyl)-piperidin-4-yl]-benzamide400 41

3-[1-(4′-Fluoro-biphenyl-4-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide417 42

3-{1-[4-(4-Fluoro-benzyloxy)-benzyl]-3R,4R-dimethyl-piperidin-4-yl}-benzamide447 43

3-{1-[4-(3-Dimethylamino-propoxy)-benzyl]-3R,4R-dimethyl-piperidin-4-yl}-benzamide424 44

3-[1-(4′-Fluoro-biphenyl-3-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide417 45

3-[1-(2-Ethoxycarbonyl-cyclopropylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide359 46

3-[1-(1-Benzenesulfonyl-1H-pyrrol-2-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide452 47

3-{3R,4R-Dimethyl-1-[1-(2-morpholin-4-yl-ethyl)-1H-pyrrol-2-ylmethyl]-piperidin4-yl}-benzamide425 48

3-[1-(1-Isoxazol-3-yl-1H-pyrrol-2-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide379 49

3-(1-Bicyclo[2.2.1]hept-5-en-2-ylmethyl-3R,4R-dimethyl-piperidin-4-yl)-benzamide339 50

3-[3R,4R-Dimethyl-1-(4-methylsulfanyl-benzyl)-piperidin-4-yl]-benzamide339 51

3-(1′-Benzyl-3R,4R,3′-trimethyl-[1,4′]bipiperidinyl-4-yl)-benzamide 42052

3-{1-[1-(5-Chloro-pyridin-2-yl)-1H-pyrrol-2-ylmethyl]-3R,4R-dimethyl-piperidin-4-yl}-benzamide423 53

3-[1-(1-Benzyl-pyrrolidin-3-yl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide392 54

3-(1-Cyclopentyl-3R,4R-dimethyl-piperidin-4-yl)-benzamide 301 55

3-{3R,4R-Dimethyl-1-[4-(2H-tetrazol-5-yl)-benzyl]-piperidin-4-yl}-benzamide391 56

3-[1-(5-Benzyloxy-1H-indol-3-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide468 57

3-{3R,4R-Dimethyl-1-[5-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-thiophen-2-ylmethyl]-piperidin-4-yl}-benzamide477 58

[[2(R)-[[4(R)-(3-amidophenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]aceticAcid 424 59

3-(1-{2-[3-(4-Hydroxyphenyl)-propionylamino]-3-methyl-butyl}-3R,4R-dimethyl-piperidin-4-yl)benzamide466

TABLE 3 DERIVATIVES OF FORMULA I (R¹ is NH₂) Example Structure Name [M +H]⁺ 60

[[2(R)-[[4(R)-(3-aminophenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]aceticAcid 424

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The disclosures of each patent,patent application and publication cited or described in this documentare hereby incorporated herein by reference, in their entirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

1. A compound of formula I:

wherein: R¹ is —C(═O)OR⁵, —C(═O)NR⁶R⁷, —NR⁶R⁷, or —CH₂OR⁵; R² and R³ areeach independently alkyl or alkenyl; R⁴ is: cycloalkyl,heterocycloalkyl, or C₁₋₁₀ alkyl which is substituted with at least one:substituted aryl, wherein at least one of said aryl substituents isother than OH, nitro, amino, halo, CN, CH₂CN, CONH₂, C₁₋₄ alkyl, C₁₋₄alkoxy, or C₁₋₅ alkanoyl (which latter three groups are optionallysubstituted by one or more halo atoms), aryloxyaryl, -aryl-N(H)R^(b),-aryl-N(R^(b))R^(b), heteroarylaryl, alkoxyaryl, wherein the carbonchain of said alkoxy is interrupted by a nitrogen atom, substitutedalkoxyaryl, provided that when one or more substituents are present onthe alkoxy group, at least one of said substituents is other than halo,substituted cycloalkyl, RS(═O)_(p) substituted heteroaryl, RS(═O)_(p)substituted heterocycloalkyl, RS(═O)_(p) substituted aryl,heterocycloalkylheteroaryl, heteroarylheteroaryl, bicycloalkyl,bicycloalkenyl, carboxy, —CO₂R^(a), —C(═O)N(R^(6a))—R^(6b)—CO₂H,—C(═O)N(R^(6a))—R^(6b)—CO₂R, —C(═O)N(R^(6a))—R^(6b)—C(═O)NR^(7a)R^(7b),—N(R^(7c))C(═O)R^(7d), aralkoxyaryl, substituted arylheteroaryl, orsubstituted alkoxyheteroaryl, provided that when one or moresubstituents are present on the alkoxy group, at least one of saidsubstituents is other than halo; p is 0, 1, or 2; R is alkyl, aralkyl,or aryl; R^(a) is H, alkyl, alkenyl, cycloalkyl, aryl, or heteroaryl,provided that R^(a) is not C₁₋₆ alkyl; each R^(b) is independentlyalkyl, cycloalkyl, aralkyl, or aryl, R^(6a) is H, alkyl, aralkyl,cycloalkyl, alkenyl, aryl, heteroaralkyl, or heteroaryl; R^(6b) is loweralkylene, or lower aralkylene or, together with the nitrogen atom towhich they are attached, R^(6a) and R^(6b) form a 4- to 7-memberedheterocycloalkyl ring; R^(7a) and R^(7b) are each independently H,alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aralkyl, or aryl, ortogether with the nitrogen atom to which they are attached, R^(7a) andR^(7b) form a 4- to 7-membered heterocycloalkyl ring, provided that atleast one of R^(7a) and R^(7b) is other than H; R^(7c) and R^(7d) areeach independently H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl,aralkyl, or aryl; R⁵ is H or alkyl; and each R⁶ and R⁷ is independentlyH, alkyl, or —C(═O)R, or, together with the nitrogen atom to which theyare attached, R⁶ and R⁷ form a 4- to 7-membered heterocycloalkyl ring,provided that no more than one of R⁶ and R⁷ is —C(═O)R, and providedthat when R¹ is NR⁶R⁷, R⁴ can also be aralkyl; or a stereoisomer,pharmaceutically acceptable salt, acid or N-oxide thereof, provided thatR² and R³ are not in the cis stereoisomer conformation when both R² andR³ are methyl.
 2. A compound according to claim 1, wherein: R⁴ is:cycloalkyl, heterocycloalkyl, or C₁₋₁₀ alkyl which is substituted withat least one: substituted aryl, wherein said aryl substituent is otherthan OH, nitro, amino, halo, CN, CH₂CN, CONH₂, C₁₋₄ alkyl, C₁₋₄ alkoxy,or C₁₋₅ alkanoyl (which latter three groups are optionally substitutedby one or more halo atoms), aryloxyaryl, -aryl-N(H)R^(b),-aryl-N(R^(b))R^(b), heteroarylaryl, alkoxyaryl, wherein the carbonchain of said alkoxy is interrupted by a nitrogen atom, substitutedalkoxyaryl, provided that when one or more substituents are present onthe alkoxy group, at least one of said substituents is other than halo,substituted cycloalkyl, RS(═O)_(p) substituted heteroaryl, RS(═O)_(p)substituted heterocycloalkyl, RS(═O)_(p) substituted aryl,heterocycloalkylheteroaryl, heteroarylheteroaryl, bicycloalkyl,bicycloalkenyl, carboxy, —CO₂R^(a), —C(═O)N(R^(6a))—R^(6b)—CO₂H,—C(═O)N(R^(6a))—R^(6b)—CO₂R, —C(═O)N(R^(6a))—R^(6b)—C(═O)NR^(7a)R^(7b),—N(R^(7c))C(═O)R^(7d), aralkoxyaryl, substituted arylheteroaryl, orsubstituted alkoxyheteroaryl, provided that when one or moresubstituents are present on the alkoxy group, at least one of saidsubstituents is other than halo.
 3. A compound according to claim 2:wherein: R⁴ is: cycloalkyl, heterocycloalkyl, or C₁₋₁₀ alkyl which issubstituted with at least one: aryloxyaryl, -aryl-N(H)R^(b),-aryl-N(R^(b))R^(b), heteroarylaryl, alkoxyaryl, wherein the carbonchain of said alkoxy is interrupted by a nitrogen atom, substitutedcycloalkyl, RS(═O)_(p) substituted heteroaryl, RS(═O)_(p) substitutedheterocycloalkyl, RS(═O)_(p) substituted aryl,heterocycloalkylheteroaryl, heteroarylheteroaryl, bicycloalkyl,bicycloalkenyl, carboxy, —CO₂R^(a), —C(═O)N(R^(6a))—R^(6b)—CO₂H,—C(═O)N(R^(6a))—R^(6b)—CO₂R, —C(═O)N(R^(6a))—R^(6b)—C(═O)NR^(7a)R^(7b),—N(R^(7c))C(═O)R^(7d), aralkoxyaryl, or substituted arylheteroaryl.
 4. Acompound according to claim 1, wherein said compound is a compound offormula Ia:


5. A compound according to claim 4, wherein R² is methyl.
 6. A compoundaccording to claim 5, wherein R³ is methyl.
 7. A compound according toclaim 6, wherein said compound is a compound of formula IIa:

wherein: R⁸ is alkyl, aralkyl, cycloalkyl, alkylcycloalkyl, aryl,heteroaryl, or heteroaralkyl; R⁹ is H, alkyl, alkenyl, cycloalkyl, aryl,or heteroaryl provided that R⁹ is not C₁₋₆ alkyl; and n is an integerfrom 1 to
 3. 8. A compound according to claim 7, wherein said compoundis a compound of formula IIIa:


9. A compound according to claim 6, wherein said compound is a compoundof formula IVa:

wherein: R⁸ is alkyl, aralkyl, cycloalkyl, alkylcycloalkyl, aryl,heteroaryl, or heteroaralkyl; R¹⁰ is —R^(6b)—CO₂H, —R^(6b)—CO₂R^(10a),or —R^(6b)—C(═O)NR^(10b)R^(10c); R¹¹ is H, alkyl, alkenyl, cycloalkyl,aryl, aralkyl, heteroaralkyl or heteroaryl, or together with thenitrogen atom to which they are attached, R^(6b) and R¹¹ form a 4- to7-membered heterocycloalkyl ring; R^(10a) is alkyl or aralkyl; R^(10b)and R^(10c) are each independently H or alkyl, or together with thenitrogen atom to which they are attached, R^(10b) and R^(10c) form a 4-to 7-membered heterocycloalkyl ring, provided that at least one ofR^(10b) and R^(10c) is other than H; and n is an integer from 1 to 3.10. A compound according to claim 9, wherein said compound is a compoundof formula Va:

wherein: R¹² is H, lower alkyl, or aralkyl; R¹³ is H, alkyl, cycloalkyl,or aryl, or together with the nitrogen and carbon atoms to which theyare respectively attached, R¹² and R¹³ form a 4- to 7-memberedheterocycloalkyl ring; each R¹⁴ independently is H, alkyl, cycloalkyl oraryl; R¹⁵ is —OR¹⁶ or —NR¹⁷R¹⁸; R¹⁶, R¹⁷, and R¹⁸ are each,independently H, or alkyl or, together with the nitrogen atom to whichthey are attached, R¹⁷ and R¹⁸ form a 4- to 7-membered heterocycloalkylring, provided that at least one of R¹⁷ and R¹⁸ is other than H; and mis an integer from 0 to
 3. 11. A compound according to claim 6, whereinsaid compound is a compound of formula VIa:

wherein: R⁸ is alkyl, aralkyl, cycloalkyl, alkylcycloalkyl, or aryl; R¹⁹is H, alkyl, cycloalkyl, or aryl; R²⁰ is —C(═O)R²¹, or —S(═O)₂R²¹; R²¹is alkyl, cycloalkyl, heterocycloalkyl, aralkyl, aryl, or heteroaryl; mis an integer from 0 to 3; and n is an integer from 1 to
 3. 12. Acompound according to claim 11, wherein said compound is a compound offormula VIIa:

wherein: R¹⁹ is H or alkyl.
 13. A compound according to claim 1, whereinR¹ is —C(═O)OR⁵, —C(═O)NR⁶R⁷, or —NR⁶R⁷; and R⁴ is C₁₋₁₀ alkyl, which issubstituted with —N(R^(7c))C(═O)R^(7d), —C(═O)N(R^(6a))R^(6b)—CO₂H, or—C(═O)N(R^(6a))—R^(6b)—CO₂R.
 14. A compound according to claim 13,wherein R⁴ is C₁₋₁₀ alkyl, which is substituted with—N(R^(7c))C(═O)R^(7d).
 15. A compound according to claim 14 wherein R⁵,R⁶, and R⁷ are H.
 16. A compound according to claim 13, wherein R⁴ isC₁₋₁₀ alkyl, which is substituted with —C(═O)N(R^(6a))—R^(6b)—CO₂H. 17.A compound according to claim 16, wherein R⁵, R⁶, and R⁷ are H.
 18. Acompound of claim 13, wherein R⁴ is C₁₋₁₀ alkyl, which is substitutedwith —C(═O)N(R^(6a))—R^(6b)—CO₂R.
 19. A compound according to claim 18,wherein R⁵, R⁶, and R⁷ are H.
 20. A compound according to claim 6,wherein R¹ is —C(═O)OR⁵, —C(═O)NR⁶R⁷, or —NR⁶R⁷; and R⁴ is C₁₋₁₀ alkyl,which is substituted with —N(R^(7c))C(═O)R^(7d),—C(═O)N(R^(6a))—R^(6b)—CO₂H, or —C(═O)N(R^(6a))—R^(6b)—CO₂R.
 21. Acompound according to claim 20, wherein R⁴ is C₁₋₁₀ alkyl, which issubstituted with —N(R^(7c))C(═O)R^(7d).
 22. A compound according toclaim 21 wherein R⁵, R⁶, and R⁷ are H.
 23. A compound according to claim20, wherein R⁴ is C₁₋₁₀ alkyl substituted with—C(═O)N(R^(6a))—R^(6b)—CO₂H.
 24. A compound according to claim 23,wherein R⁵, R⁶, and R⁷ are H.
 25. A compound of claim 20, wherein R⁴ isC₁₋₁₀ alkyl substituted with —C(═O)N(R^(6a))—R^(6b)—CO₂R.
 26. A compoundof claim 25, wherein R⁵, R⁶, and R⁷ are H.
 27. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier; and aneffective amount of a compound according to claim
 1. 28. Apharmaceutical composition according to claim 27, further comprising aneffective amount of at least one opioid.
 29. A pharmaceuticalcomposition according to claim 28, wherein said opioid is selected fromalfentanil, buprenorphine, butorphanol, codeine, dezocine,dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol,meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone,oxymorphone, pentazocine, propiram, propoxyphene, sufentanil, tramadolor mixtures thereof.
 30. A method for treating gastrointestinaldysfunction caused by an endogenous or exogenous opioid, comprising thestep of: administering to a mammal in need of such treatment, acomposition comprising an effective amount of a compound according toclaim
 1. 31. A method for treating post-operative or opioid-inducedileus, comprising the step of: administering to a mammal in need of suchtreatment, a composition comprising an effective amount of a compoundaccording to claim
 1. 32. A method for treating at least one side effectassociated with an opioid, comprising the step of: administering to amammal in need of such treatment, a composition comprising an effectiveamount of a compound according to claim 1; wherein said side effect isselected from the group consisting of constipation, nausea, andvomiting.
 33. A method according to claim 32, wherein said compositionfurther comprises an effective amount of at least one opioid.
 34. Amethod according to claim 32, wherein said administering step occursbefore, during or after a step of administering at least one opioid. 35.A method of treating pain, comprising the step of: administering to amammal in need thereof, a composition, comprising: an effective amountof an opioid; and an effective amount of a compound according toclaim
 1. 36. A method according to claim 33 or 35, wherein said opioidis selected from alfentanil, buprenorphine, butorphanol, codeine,dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone,levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine,oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil,tramadol or mixtures thereof.
 37. A compound selected from the groupconsisting of: 3-(1-cyclohexyl-3R,4R-dimethyl-piperidin-4-yl)-benzoicacid; 3-[1-(3-benzyloxy-benzyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoicacid; 3-(1-biphenyl-4-ylmethyl-3R,4R-dimethyl-piperidin-4-yl)-benzoicacid; 3-[3R,4R-dimethyl-1-(3-phenoxy-benzyl)-piperidin-4-yl]-benzoicacid;3-[1-(4-dimethylamino-benzyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoicacid;3-[3R,4R-dimethyl-1-(2-pyridin-4-yl-benzyl)-piperidin-4-yl]-benzoicacid;3-{1-[4-(4-fluoro-phenoxy)-benzyl]-3R,4R-dimethyl-piperidin-4-yl}-benzoicacid;3-[3R,4R-dimethyl-1-(4-pyrimidin-5-yl-benzyl)-piperidin-4-yl]-benzoicacid;3-[3R,4R-dimethyl-1-(4-pyridin-3-yl-benzyl)-piperidin-4-yl]-benzoicacid;3-[3R,4R-dimethyl-1-(4-pyridin-4-yl-benzyl)-piperidin-4-yl]-benzoicacid;3-{1-[4-(3-dimethylamino-propoxy)-benzyl]-3R,4R-dimethyl-piperidin-4-yl}-benzoicacid;3-{1-[4-(4-fluoro-benzyloxy)-benzyl]-3R,4R-dimethyl-piperidin-4-yl}-benzoicacid;3-[1-(4′-fluoro-biphenyl-4-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoicacid;3-[1-(4′-fluoro-biphenyl-3-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoicacid;3-[1-(2-ethoxycarbonyl-cyclopropylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoicacid;3-[1-(1-benzenesulfonyl-1H-pyrrol-2-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoicacid;3-{3R,4R-dimethyl-1-[1-(2-morpholin-4-yl-ethyl)-1H-pyrrol-2-ylmethyl]-piperidin-4-yl}-benzoicacid;3-[1-(1-isoxazol-3-yl-1H-pyrrol-2-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoicacid; 3-(1-bicyclo [2.2.1]hept-5-en-2-ylmethyl-3R,4R-dimethyl-piperidin-4-yl)-benzoic acid;3-[3R,4R-dimethyl-1-(4-methylsulfanyl-benzyl)-piperidin-4-yl]-benzoicacid; 3-(3R,4R,1′-trimethyl-[1,4′]bipiperidinyl-4-yl)-benzoic acid;3-(1′-benzyl-3R,4R,3′-trimethyl-[1,4′]bipiperidinyl-4-yl)-benzoic acid;3-[1-(1-benzyl-pyrrolidin-3-yl)-3R,4R-dimethyl-piperidin-4-yl]-benzoicacid; 3-(1-cyclopentyl-3R,4R-dimethyl-piperidin-4-yl)-benzoic acid;3-[1-(2S-carboxy-3-phenyl-propyl)-3R,4R-dimethyl-piperidin-4-yl]-benzoicacid;[[2(R)-[[4(R)-(3-carboxyphenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenyipropyl]amino]aceticacid;3-(1-{2-[3-(4-hydroxyphenyl)-propionylamino]-3-methyl-butyl}-3R,4R-dimethyl-piperidin-4-yl)benzoicacid; 3-(1-cyclohexyl-3R,4R-dimethyl-piperidin-4-yl)-benzamide;3-[1-(3-benzyloxy-benzyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide;3-(1-biphenyl-4-ylmethyl-3R,4R-dimethyl-piperidin-4-yl)-benzamide;3-[3R,4R-dimethyl-1-(3-phenoxy-benzyl)-piperidin-4-yl]-benzamide;3-[1-(4-dimethylamino-benzyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide;3-[3R,4R-dimethyl-1-(2-pyridin-4-yl-benzyl)-piperidin-4-yl]-benzamide;3-{1-[4-(4-fluoro-phenoxy)-benzyl]-3R,4R-dimethyl-piperidin-4-yl}-benzamide;3-[3R,4R-dimethyl-1-(4-pyrimidin-5-yl-benzyl)-piperidin-4-yl]-benzamide;3-[3R,4R-dimethyl-1-(4-pyridin-3-yl-benzyl)-piperidin-4-yl]-benzamide;3-[3R,4R-dimethyl-1-(4-pyridin-4-yl-benzyl)-piperidin-4-yl]-benzamide;3-[1-(4′-fluoro-biphenyl-4-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide;3-{1-[4-(4-fluoro-benzyloxy)-benzyl]-3R,4R-dimethyl-piperidin-4-yl}-benzamide;3-{1-[4-(3-dimethylamino-propoxy)-benzyl]-3R,4R-dimethyl-piperidin-4-yl}1-benzamide;3-[1-(4′-fluoro-biphenyl-3-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide;3-[1-(2-ethoxycarbonyl-cyclopropylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide;3-[1-(1-benzenesulfonyl-1H-pyrrol-2-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide;3-{3R,4R-dimethyl-1-[1-(2-morpholin-4-yl-ethyl)-1H-pyrrol-2-ylmethyl]-piperidin-4-yl}-benzamide;3-[1-(1-isoxazol-3-yl-1H-pyrrol-2-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide;3-(1-bicyclo [2.2.1]hept-5-en-2-ylmethyl-3R,4R-dimethyl-piperidin-4-yl)-benzamide;3-[3R,4R-dimethyl-1-(4-methylsulfanyl-benzyl)-piperidin-4-yl]-benzamide;3-(1′-benzyl-3R,4R,3′-trimethyl-[1,4′]bipiperidinyl-4-yl)-benzamide;3-{1-[1-(5-chloro-pyridin-2-yl)-1H-pyrrol-2-ylmethyl]-3R,4R-dimethyl-piperidin-4-yl}-benzamide;3-[1-(1-benzyl-pyrrolidin-3-yl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide;3-(1-cyclopentyl-3R,4R-dimethyl-piperidin-4-yl)-benzamide;3-{3R,4R-dimethyl-1-[4-(2H-tetrazol-5-yl)-benzyl]-piperidin-4-yl}-benzamide;3-[1-(5-benzyloxy-1H-indol-3-ylmethyl)-3R,4R-dimethyl-piperidin-4-yl]-benzamide;3-{3R,4R-dimethyl-1-[5-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-thiophen-2-ylmethyl]-piperidin-4-yl}-benzamide;[[2(R)-[[4(R)-(3-amidophenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]aceticacid;3-(1-{2-[3-(4-hydroxyphenyl)-propionylamino]-3-methyl-butyl}-3R,4R-dimethyl-piperidin-4-yl)benzamide;[[2(R)-[[4(R)-(3-aminophenyl)-3(R),4-dimethyl-1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]amino]aceticacid; and pharmaceutically acceptable salts thereof.